Louanne Hudgins
Professor of Pediatrics (Genetics) at the Lucile Salter Packard Children's Hospital, Emerita
Pediatrics - Medical Genetics
Honors & Awards
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Mosbacher Family Distinguished Packard Fellow, Stanford University School of Medicine, Department of Pediatrics (2008-present)
Current Research and Scholarly Interests
I am interested in prenatal genetic screening and diagnosis.
2023-24 Courses
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Independent Studies (5)
- Directed Reading in Pediatrics
PEDS 299 (Aut, Win, Spr, Sum) - Early Clinical Experience
PEDS 280 (Aut, Win, Spr, Sum) - Graduate Research
PEDS 399 (Aut, Win, Spr, Sum) - Medical Scholars Research
PEDS 370 (Aut, Win, Spr, Sum) - Undergraduate Directed Reading/Research
PEDS 199 (Aut, Win, Spr, Sum)
- Directed Reading in Pediatrics
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Prior Year Courses
2021-22 Courses
- Introduction to Medical Genetics
CHPR 272, GENE 272 (Aut)
- Introduction to Medical Genetics
All Publications
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Medical genetics education for pediatrics residents: Abrief report.
Genetics in medicine : official journal of the American College of Medical Genetics
2022
Abstract
PURPOSE: Genetic testing is ubiquitous in the field of medicine and is often ordered or requested by primary care providers, nongenetics subspecialists, and patients themselves. Other studies have shown that providers are often not comfortable ordering genetic testing. There have been initiatives to teach these concepts via continuing medical education; however, there is not a standardized training program for teaching resident physicians about genetic testing.METHODS: During September to October 2020, we recruited all the pediatrics residents at our institution via email (N= 102). Residents were invited to complete a Qualtrics electronic survey that addressed self-perceived level of knowledge about core concepts of genetic testing, as well as self-perceived confidence discussing these concepts with families.RESULTS: Response rate was 46 to 102 (45%). Proportions of respondents reporting they felt insufficiently knowledgeable ranged from 28% (basic concepts of genetics) to 80% (Genetic Information Nondiscrimination Act). Most pediatrics residents agreed that a curriculum teaching basics of genetic testing would be helpful to them. Desired curricular topics included indications and limitations of genetic testing, testing procedures, and counseling families.CONCLUSION: Despite its expanding importance across medicine, genetics education is lacking in pediatrics residency programs and residents would benefit from a curriculum teaching basic concepts of genetic testing.
View details for DOI 10.1016/j.gim.2022.08.003
View details for PubMedID 36029300
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RASopathies: A significant cause of polyhydramnios?
Prenatal diagnosis
2020
Abstract
OBJECTIVE: The aim of the study is to determine the prevalence of RASopathies in a polyhydramnios cohort selected by postnatal medical genetics evaluation.METHODS: In this retrospective study, we reviewed 622 pregnancies with polyhydramnios seen at Lucile Packard Children's Hospital between 2008-2017. The findings from 131 cases evaluated by Medical Genetics were included in our final analysis. Genetic testing information was extracted to determine the rate of chromosomal or single gene conditions focusing on the RASopathies. Additional variables collected were: maternal characteristics, ultrasound findings, and the severity and timing of diagnosis of polyhydramnios.RESULTS: Postnatal genetic testing or clinical examination identified a genetic disorder in 63 (48.1%) cases, more than half (n=33) of which had a single gene condition. Postnatal testing revealed an underlying RASopathy in 15 (11.5%) cases. An underlying RASopathy was significantly associated with the severity and timing of polyhydramnios (p<0.05).CONCLUSION: Focusing on a selected cohort postnatally evaluated by Medical Genetics, our study identified a chromosomal or genetic disorder in almost half of pregnancies complicated by polyhydramnios. Specifically, an underlying RASopathy was found in 11.5% of cases with 13/15 of these cases having additional ultrasound findings. This article is protected by copyright. All rights reserved.
View details for DOI 10.1002/pd.5862
View details for PubMedID 33150592
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Cobblestone Malformation in LAMA2 Congenital Muscular Dystrophy (MDC1A).
Journal of neuropathology and experimental neurology
2020
Abstract
Congenital muscular dystrophy type 1A (MDC1A) is caused by recessive variants in laminin alpha2 (LAMA2). Patients have been found to have white matter signal abnormalities on magnetic resonance imaging (MRI) but rarely structural brain abnormalities. We describe the autopsy neuropathology in a 17-year-old with white matter signal abnormalities on brain MRI. Dystrophic pathology was observed in skeletal muscle, and the sural nerve manifested a mild degree of segmental demyelination and remyelination. A diffuse, bilateral cobblestone appearance, and numerous points of fusion between adjacent gyri were apparent on gross examination of the cerebrum. Brain histopathology included focal disruptions of the glia limitans associated with abnormal cerebral cortical lamination or arrested cerebellar granule cell migration. Subcortical nodular heterotopia was present within the cerebellar hemispheres. Sampling of the centrum semiovale revealed no light microscopic evidence of leukoencephalopathy. Three additional MDC1A patients were diagnosed with cobblestone malformation on brain MRI. Unlike the autopsied patient whose brain had a symmetric distribution of cobblestone pathology, the latter patients had asymmetric involvement, most severe in the occipital lobes. These cases demonstrate that cobblestone malformation may be an important manifestation of the brain pathology in MDC1A and can be present even when patients have a structurally normal brain MRI.
View details for DOI 10.1093/jnen/nlaa062
View details for PubMedID 32827036
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Addendum: Array-based technology and recommendations for utilization in medical genetics practice for detection of chromosomal abnormalities.
Genetics in medicine : official journal of the American College of Medical Genetics
2020
View details for DOI 10.1038/s41436-020-0848-8
View details for PubMedID 32514088
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Correction: KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants.
Genetics in medicine : official journal of the American College of Medical Genetics
2020
Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
View details for DOI 10.1038/s41436-020-00944-7
View details for PubMedID 32814847
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DYRK1A-related intellectual disability: a syndrome associated with congenital anomalies of the kidney and urinary tract.
Genetics in medicine : official journal of the American College of Medical Genetics
2019
Abstract
PURPOSE: Haploinsufficiency of DYRK1A causes a recognizable clinical syndrome. The goal of this paper is to investigate congenital anomalies of the kidney and urinary tract (CAKUT) and genital defects (GD) in patients with DYRK1A variants.METHODS: A large database of clinical exome sequencing (ES) was queried for de novo DYRK1A variants and CAKUT/GD phenotypes were characterized. Xenopus laevis (frog) was chosen as a model organism to assess Dyrk1a's role in renal development.RESULTS: Phenotypic details and variants of 19 patients were compiled after an initial observation that one patient with a de novo pathogenic variant in DYRK1A had GD. CAKUT/GD data were available from 15 patients, 11 of whom presented with CAKUT/GD. Studies in Xenopus embryos demonstrated that knockdown of Dyrk1a, which is expressed in forming nephrons, disrupts the development of segments of embryonic nephrons, which ultimately give rise to the entire genitourinary (GU) tract. These defects could be rescued by coinjecting wild-type human DYRK1A RNA, but not with DYRK1AR205* or DYRK1AL245R RNA.CONCLUSION: Evidence supports routine GU screening of all individuals with de novo DYRK1A pathogenic variants to ensure optimized clinical management. Collectively, the reported clinical data and loss-of-function studies in Xenopus substantiate a novel role for DYRK1A in GU development.
View details for DOI 10.1038/s41436-019-0576-0
View details for PubMedID 31263215
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Prenatally diagnosed omphalocele: characteristics associated with adverse neonatal outcomes.
Journal of perinatology : official journal of the California Perinatal Association
2019
Abstract
OBJECTIVE: To characterize factors associated with adverse neonatal outcomes in prenatally diagnosed omphalocele cases.STUDY DESIGN: Prenatally diagnosed omphalocele cases at a single referral center from 1 January 2009 to 31 December 2017 were retrospectively reviewed. Clinical variables and antenatal imaging measurements were collected. Associations between prenatal and neonatal characteristics and the adverse outcome of death or prolonged length of stay (LOS) were analyzed.RESULTS: Out of 63 fetal cases, 33 were live-born, >50% had other anomalies, and neonatal mortality was 12%. Adverse outcomes were associated with neonatal variables, including lower median 1-min Apgar score, initial mechanical ventilation, and late-onset sepsis, but not approach toomphalocele closure. With multivariate analysis, death or prolonged LOS was associated only with low lung volumes by fetal MRI (OR 34 (3-422), p=0.006).CONCLUSION: Low lung volumes by fetal MRI were associated with death or prolonged LOS in neonates with prenatally diagnosed omphalocele and may guide clinicians with counseling families.
View details for DOI 10.1038/s41372-019-0410-1
View details for PubMedID 31227786
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Developing a conceptual, reproducible, rubric-based approach to consent and result disclosure for genetic testing by clinicians with minimal genetics background
GENETICS IN MEDICINE
2019; 21 (3): 727–35
View details for DOI 10.1038/s41436-018-0093-6
View details for Web of Science ID 000460274400028
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Cornelia de Lange syndrome in diverse populations.
American journal of medical genetics. Part A
2019
Abstract
Cornelia de Lange syndrome (CdLS) is a dominant multisystemic malformation syndrome due to mutations in five genes-NIPBL, SMC1A, HDAC8, SMC3, and RAD21. The characteristic facial dysmorphisms include microcephaly, arched eyebrows, synophrys, short nose with depressed bridge and anteverted nares, long philtrum, thin lips, micrognathia, and hypertrichosis. Most affected individuals have intellectual disability, growth deficiency, and upper limb anomalies. This study looked at individuals from diverse populations with both clinical and molecularly confirmed diagnoses of CdLS by facial analysis technology. Clinical data and images from 246 individuals with CdLS were obtained from 15 countries. This cohort included 49% female patients and ages ranged from infancy to 37years. Individuals were grouped into ancestry categories of African descent, Asian, Latin American, Middle Eastern, and Caucasian. Across these populations, 14 features showed a statistically significant difference. The most common facial features found in all ancestry groups included synophrys, short nose with anteverted nares, and a long philtrum with thin vermillion of the upper lip. Using facial analysis technology we compared 246 individuals with CdLS to 246 gender/age matched controls and found that sensitivity was equal or greater than 95% for all groups. Specificity was equal or greater than 91%. In conclusion, we present consistent clinical findings from global populations with CdLS while demonstrating how facial analysis technology can be a tool to support accurate diagnoses in the clinical setting. This work, along with prior studies in this arena, will assist in earlier detection, recognition, and treatment of CdLS worldwide.
View details for PubMedID 30614194
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Correction: DYRK1A-related intellectual disability: a syndrome associated with congenital anomalies of the kidney and urinary tract.
Genetics in medicine : official journal of the American College of Medical Genetics
2019
Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
View details for DOI 10.1038/s41436-019-0732-6
View details for PubMedID 31857706
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Clinical spectrum of individuals with pathogenic NF1 missense variants affecting p.Met1149, p.Arg1276 and p.Lys1423: genotype-phenotype study in neurofibromatosis type 1.
Human mutation
2019
Abstract
We report 281 individuals carrying a pathogenic recurrent NF1 missense variants at p.Met1149, p.Arg1276 or p.Lys1423, representing three non-truncating NF1 hotspots in the University of Alabama at Birmingham (UAB) cohort, together identified in 1.8% of unrelated NF1 individuals. About 25% (95% CI, 20.5%-31.2%) of individuals heterozygous for a pathogenic NF1 p.Met1149, p.Arg1276 or p.Lys1423 missense variant had a Noonan-like phenotype, which is significantly more compared to the "classic" NF1-affected cohorts (all P<0.0001). Furthermore, p.Arg1276 and p.Lys1423 pathogenic missense variants were associated with a high prevalence of cardiovascular abnormalities, including pulmonic stenosis (all P<0.0001), while p.Arg1276 variants had a high prevalence of symptomatic spinal neurofibromas (P<0.0001) compared with "classic" NF1-affected cohorts. However, p.Met1149-positive individuals had a mild phenotype, characterized mainly by pigmentary manifestations without externally visible plexiform neurofibromas, symptomatic spinal neurofibromas or symptomatic optic pathway gliomas. As up to 0.4% of unrelated individuals in the UAB cohort carries a p.Met1149 missense variant, this finding will contribute to more accurate stratification of a significant number of NF1 individuals. Although clinically relevant genotype-phenotype correlations are rare in NF1, each affecting only a small percentage of individuals, together they impact counseling and management of a significant number of the NF1 population. This article is protected by copyright. All rights reserved.
View details for DOI 10.1002/humu.23929
View details for PubMedID 31595648
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Perinatal distress in 1p36 deletion syndrome can mimic hypoxic ischemic encephalopathy.
American journal of medical genetics. Part A
2019
Abstract
1p36 deletion syndrome is a well-described condition with a recognizable phenotype, including cognitive impairment, seizures, and structural brain anomalies such as periventricular leukomalacia (PVL). In a large series of these individuals by Battaglia et al., "birth history was notable in 50% of the cases for varying degrees of perinatal distress." Given the potential for perinatal distress, seizures and PVL, we questioned if this disorder has clinical overlap with hypoxic ischemic encephalopathy (HIE). We reviewed the medical records of 69 individuals with 1p36 deletion to clarify the perinatal phenotype of this disorder and determine if there is evidence of perinatal distress and/or hypoxic injury. Our data provides evidence that these babies have signs of perinatal distress. The majority (59% term; 75% preterm) needed resuscitation and approximately 18% had cardiac arrest. Most had abnormal brain imaging (84% term; 73% preterm) with abnormal white matter findings in over half of patients. PVL or suggestion of "hypoxic insult" was present in 18% of term and 45% of preterm patients. In conclusion, individuals with 1p36 deletion have evidence of perinatal distress, white matter changes, and seizures, which can mimic HIE but are likely related to their underlying chromosome disorder.
View details for DOI 10.1002/ajmg.a.61266
View details for PubMedID 31207089
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Annemarie Sommer memorial.
American journal of medical genetics. Part A
2019
View details for DOI 10.1002/ajmg.a.61287
View details for PubMedID 31321866
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Autosomal recessive Stickler syndrome resulting from a COL9A3 mutation
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
2018; 176 (12): 2887-2891
View details for DOI 10.1002/ajmg.a.40647
View details for Web of Science ID 000454612700052
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Autosomal recessive Stickler syndrome resulting from a COL9A3 mutation.
American journal of medical genetics. Part A
2018
Abstract
Stickler syndrome is a connective tissue disorder characterized by hearing loss, ocular anomalies, palatal defects, and skeletal abnormalities. The autosomal dominant form is the most common, but autosomal recessive forms have also been described. We report the second case of autosomal recessive Stickler syndrome due to homozygosity for a loss of function mutation in COL9A3, which encodes the alpha3 chain of type IX procollagen. The clinical features were similar to the previously described COL9A3 Stickler syndrome family, including moderate to severe sensorineural hearing loss, high myopia, and both tibial and femoral bowing at birth. Radiographs demonstrated abnormal capital femoral epiphyses and mild irregularities of the vertebral endplates. This case further establishes the phenotype associated with mutations in this gene. We suggest that loss of the alpha3 chain of type IX collagen results in a Stickler syndrome phenotype similar to that of the other autosomal recessive forms caused by mutations in genes encoding the alpha1 and alpha2 chains of type IX collagen.
View details for PubMedID 30450842
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Developing a conceptual, reproducible, rubric-based approach to consent and result disclosure for genetic testing by clinicians with minimal genetics background.
Genetics in medicine : official journal of the American College of Medical Genetics
2018
Abstract
PURPOSE: In response to genetic testing being widely ordered by nongenetics clinicians, the Consent and Disclosure Recommendations (CADRe) Workgroup of the Clinical Genome Resource (ClinGen; clinicalgenome.org ) developed guidance to facilitate communication about genetic testing and efficiently improve the patient experience. Considering ethical, legal, and social implications, and medical factors, CADRe developed and pilot tested two rubrics addressing consent for genetic testing and results disclosure. The CADRe rubrics allow for adjusting the communication approach based on circumstances specific to patients and ordering clinicians.METHODS: We present results of a formative survey of 66 genetics clinicians to assess the consent rubric for nine genes (MLH1, CDH1, TP53, GJB2, OTC; DMD, HTT, and CYP2C9/VKORC1). We also conducted interviews and focus groups with family and patient stakeholders (N=18), nongenetics specialists (N=27), and genetics clinicians (N=32) on both rubrics.RESULTS: Formative evaluation of the CADRe rubrics suggests key factors on which to make decisions about consent and disclosure discussions for a "typical" patient.CONCLUSION: We propose that the CADRe rubrics include the primary issues necessary to guide communication recommendations, and are ready for pilot testing by nongenetics clinicians. Consultation with genetics clinicians can be targeted toward more complex or intensive consent and disclosure counseling.
View details for PubMedID 29976988
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ERCC4 variants identified in a cohort of patients with segmental progeroid syndromes
HUMAN MUTATION
2018; 39 (2): 255–65
Abstract
Pathogenic variants in genes, which encode DNA repair and damage response proteins, result in a number of genomic instability syndromes with features of accelerated aging. ERCC4 (XPF) encodes a protein that forms a complex with ERCC1 and is required for the 5' incision during nucleotide excision repair. ERCC4 is also FANCQ, illustrating a critical role in interstrand crosslink repair. Pathogenic variants in this gene cause xeroderma pigmentosum, XFE progeroid syndrome, Cockayne syndrome (CS), and Fanconi anemia. We performed massive parallel sequencing for 42 unsolved cases submitted to the International Registry of Werner Syndrome. Two cases, each carrying two novel heterozygous ERCC4 variants, were identified. The first case was a compound heterozygote for: c.2395C > T (p.Arg799Trp) and c.388+1164_792+795del (p.Gly130Aspfs*18). Further molecular and cellular studies indicated that the ERCC4 variants in this patient are responsible for a phenotype consistent with a variant of CS. The second case was heterozygous for two variants in cis: c.[1488A > T; c.2579C > A] (p.[Gln496His; Ala860Asp]). While the second case also had several phenotypic features of accelerated aging, we were unable to provide biological evidence supporting the pathogenic roles of the associated ERCC4 variants. Precise genetic causes and disease mechanism of the second case remains to be determined.
View details for PubMedID 29105242
View details for PubMedCentralID PMC5762268
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Noninvasive Prenatal Diagnosis of Single-Gene Disorders by Use of Droplet Digital PCR.
Clinical chemistry
2018; 64 (2): 336-345
Abstract
Prenatal diagnosis in pregnancies at risk of single-gene disorders is currently performed using invasive methods such as chorionic villus sampling and amniocentesis. This is in contrast with screening for common aneuploidies, for which noninvasive methods with a single maternal blood sample have become standard clinical practice.We developed a protocol for noninvasive prenatal diagnosis of inherited single-gene disorders using droplet digital PCR from circulating cell-free DNA (cfDNA) in maternal plasma. First, the amount of cfDNA and fetal fraction is determined using a panel of TaqMan assays targeting high-variability single-nucleotide polymorphisms. Second, the ratio of healthy and diseased alleles in maternal plasma is quantified using TaqMan assays targeting the mutations carried by the parents. Two validation approaches of the mutation assay are presented.We collected blood samples from 9 pregnancies at risk for different single-gene disorders, including common conditions and rare metabolic disorders. We measured cases at risk of hemophilia, ornithine transcarbamylase deficiency, cystic fibrosis, β-thalassemia, mevalonate kinase deficiency, acetylcholine receptor deficiency, and DFNB1 nonsyndromic hearing loss. We correctly differentiated affected and unaffected pregnancies (2 affected, 7 unaffected), confirmed by neonatal testing. We successfully measured an affected pregnancy as early as week 11 and with a fetal fraction as low as 3.7% (0.3).Our method detects single-nucleotide mutations of autosomal recessive diseases as early as the first trimester of pregnancy. This is of importance for metabolic disorders in which early diagnosis can affect management of the disease and reduce complications and anxiety related to invasive testing.
View details for DOI 10.1373/clinchem.2017.278101
View details for PubMedID 29097507
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Noninvasive Prenatal Diagnosis of Single-Gene Disorders by Use of Droplet Digital PCR
CLINICAL CHEMISTRY
2018; 64 (2): 336–45
View details for DOI 10.1373/clinchem.2017.278101
View details for Web of Science ID 000424396200017
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Current controversies in prenatal diagnosis 2: Cell-free DNA prenatal screening should be used to identify all chromosome abnormalities
PRENATAL DIAGNOSIS
2018; 38 (3): 160–65
Abstract
Noninvasive prenatal testing (NIPT) using cell-free DNA (cfDNA) from maternal serum has been clinically available since 2011. This technology has revolutionized our ability to screen for the common aneuploidies trisomy 21 (Down syndrome), trisomy 18, and trisomy 13. More recently, clinical laboratories have offered screening for other chromosome abnormalities including sex chromosome abnormalities and copy number variants (CNV) without little published data on the sensitivity, specificity, and positive predictive value. In this debate, the pros and cons of performing prenatal screening via cfDNA for all chromosome abnormalities is discussed. At the time of the debate in 2017, the general consensus was that the literature does not yet support using this technology to screen for all chromosome abnormalities and that education is key for both providers and the patients so that the decision-making process is as informed as possible.
View details for PubMedID 29417608
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Prenatal treatment of ornithine transcarbamylase deficiency.
Molecular genetics and metabolism
2018
Abstract
Patients with neonatal urea cycle defects (UCDs) typically experience severe hyperammonemia during the first days of life, which results in serious neurological injury or death. Long-term prognosis despite optimal pharmacological and dietary therapy is still poor. The combination of intravenous sodium phenylacetate and sodium benzoate (Ammonul®) can eliminate nitrogen waste independent of the urea cycle. We report attempts to improve outcomes for males with severe ornithine transcarbamylase deficiency (OTCD), a severe X-linked condition, via prenatal intravenous administration of Ammonul and arginine to heterozygous carrier females of OTCD during labor.Two heterozygote OTCD mothers carrying male fetuses with a prenatal diagnosis of OTCD received intravenous Ammonul, arginine and dextrose-containing fluids shortly before birth. Maintenance Ammonul and arginine infusions and high-caloric enteral nutrition were started immediately after birth. Ammonul metabolites were measured in umbilical cord blood and the blood of the newborn immediately after delivery. Serial ammonia and biochemical analyses were performed following delivery.Therapeutic concentrations of Ammonul metabolites were detected in umbilical cord and neonatal blood samples. Plasma ammonia and glutamine levels in the postnatal period were within the normal range. Peak ammonia levels in the first 24-48h were 53mcmol/l and 62mcmol/l respectively. The boys did not experience neurological sequelae secondary to hyperammonemia and received liver transplantation at ages 3months and 5months. The patients show normal development at ages 7 and 3years.Prenatal treatment of mothers who harbor severe OTCD mutations and carry affected male fetuses with intravenous Ammonul and arginine, followed by immediate institution of maintenance infusions after delivery, results in therapeutic levels of benzoate and phenylacetate in the newborn at delivery and, in conjunction with high-caloric enteral nutrition, prevents acute hyperammonemia and neurological decompensation. Following initial medical management, early liver transplantation may improve developmental outcome.
View details for PubMedID 29396029
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Clinical exome sequencing reveals locus heterogeneity and phenotypic variability of cohesinopathies.
Genetics in medicine : official journal of the American College of Medical Genetics
2018
Abstract
Defects in the cohesin pathway are associated with cohesinopathies, notably Cornelia de Lange syndrome (CdLS). We aimed to delineate pathogenic variants in known and candidate cohesinopathy genes from a clinical exome perspective.We retrospectively studied patients referred for clinical exome sequencing (CES, N = 10,698). Patients with causative variants in novel or recently described cohesinopathy genes were enrolled for phenotypic characterization.Pathogenic or likely pathogenic single-nucleotide and insertion/deletion variants (SNVs/indels) were identified in established disease genes including NIPBL (N = 5), SMC1A (N = 14), SMC3 (N = 4), RAD21 (N = 2), and HDAC8 (N = 8). The phenotypes in this genetically defined cohort skew towards the mild end of CdLS spectrum as compared with phenotype-driven cohorts. Candidate or recently reported cohesinopathy genes were supported by de novo SNVs/indels in STAG1 (N = 3), STAG2 (N = 5), PDS5A (N = 1), and WAPL (N = 1), and one inherited SNV in PDS5A. We also identified copy-number deletions affecting STAG1 (two de novo, one of unknown inheritance) and STAG2 (one of unknown inheritance). Patients with STAG1 and STAG2 variants presented with overlapping features yet without characteristic facial features of CdLS.CES effectively identified disease-causing alleles at the mild end of the cohensinopathy spectrum and enabled characterization of candidate disease genes.
View details for PubMedID 30158690
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KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants.
Genetics in medicine : official journal of the American College of Medical Genetics
2018
Abstract
Pathogenic variants in KAT6A have recently been identified as a cause of syndromic developmental delay. Within 2 years, the number of patients identified with pathogenic KAT6A variants has rapidly expanded and the full extent and variability of the clinical phenotype has not been reported.We obtained data for patients with KAT6A pathogenic variants through three sources: treating clinicians, an online family survey distributed through social media, and a literature review.We identified 52 unreported cases, bringing the total number of published cases to 76. Our results expand the genotypic spectrum of pathogenic variants to include missense and splicing mutations. We functionally validated a pathogenic splice-site variant and identified a likely hotspot location for de novo missense variants. The majority of clinical features in KAT6A syndrome have highly variable penetrance. For core features such as intellectual disability, speech delay, microcephaly, cardiac anomalies, and gastrointestinal complications, genotype- phenotype correlations show that late-truncating pathogenic variants (exons 16-17) are significantly more prevalent. We highlight novel associations, including an increased risk of gastrointestinal obstruction.Our data expand the genotypic and phenotypic spectrum for individuals with genetic pathogenic variants in KAT6A and we outline appropriate clinical management.
View details for PubMedID 30245513
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De Novo Missense Variants in TRAF7 Cause Developmental Delay, Congenital Anomalies, and Dysmorphic Features.
American journal of human genetics
2018
Abstract
TRAF7 is a multi-functional protein involved in diverse signaling pathways and cellular processes. The phenotypic consequence of germline TRAF7 variants remains unclear. Here we report missense variants in TRAF7 in seven unrelated individuals referred for clinical exome sequencing. The seven individuals share substantial phenotypic overlap, with developmental delay, congenital heart defects, limb and digital anomalies, and dysmorphic features emerging as key unifying features. The identified variants are de novo in six individuals and comprise four distinct missense changes, including a c.1964G>A (p.Arg655Gln) variant that is recurrent in four individuals. These variants affect evolutionarily conserved amino acids and are located in key functional domains. Gene-specific mutation rate analysis showed that the occurrence of the de novo variants in TRAF7 (p = 2.6 × 10-3) and the recurrent de novo c.1964G>A (p.Arg655Gln) variant (p = 1.9 × 10-8) in our exome cohort was unlikely to have occurred by chance. In vitro analyses of the observed TRAF7 mutations showed reduced ERK1/2 phosphorylation. Our findings suggest that missense mutations in TRAF7 are associated with a multisystem disorder and provide evidence of a role for TRAF7 in human development.
View details for PubMedID 29961569
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37th Annual David W. Smith Workshop on Malformations and Morphogenesis: Abstracts of the 2016 Annual Meeting.
American journal of medical genetics. Part A
2017: 2007-2073
Abstract
The 37th Annual David W. Smith Workshop on Malformations and Morphogenesis occurred on September 9th-14th, 2016 at the University of California-Los Angeles Conference Center in Lake Arrowhead, CA. The Workshop, which honors the legacy of David W. Smith, brought together clinicians and researchers interested in congenital malformations and their underlying mechanisms of morphogenesis. The Workshop highlighted five themes besides mechanisms of morphogenesis and New Syndromes: Neural Crestopathies, Mosaicism, Disorders of Skin Pigmentation, Therapies, and Ear Malformations and Hearing Loss. This Conference Report includes the abstracts presented at the 2016 Workshop.
View details for DOI 10.1002/ajmg.a.38229
View details for PubMedID 28544249
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Phenotypic and molecular characterisation of CDK13-related congenital heart defects, dysmorphic facial features and intellectual developmental disorders.
Genome medicine
2017; 9 (1): 73
Abstract
De novo missense variants in CDK13 have been described as the cause of syndromic congenital heart defects in seven individuals ascertained from a large congenital cardiovascular malformations cohort. We aimed to further define the phenotypic and molecular spectrum of this newly described disorder.To minimise ascertainment bias, we recruited nine additional individuals with CDK13 pathogenic variants from clinical and research exome laboratory sequencing cohorts. Each individual underwent dysmorphology exam and comprehensive medical history review.We demonstrate greater than expected phenotypic heterogeneity, including 33% (3/9) of individuals without structural heart disease on echocardiogram. There was a high penetrance for a unique constellation of facial dysmorphism and global developmental delay, as well as less frequently seen renal and sacral anomalies. Two individuals had novel CDK13 variants (p.Asn842Asp, p.Lys734Glu), while the remaining seven unrelated individuals had a recurrent, previously published p.Asn842Ser variant. Summary of all variants published to date demonstrates apparent restriction of pathogenic variants to the protein kinase domain with clustering in the ATP and magnesium binding sites.Here we provide detailed phenotypic and molecular characterisation of individuals with pathogenic variants in CDK13 and propose management guidelines based upon the estimated prevalence of anomalies identified.
View details for PubMedID 28807008
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A novel missense variant in the GLI3 zinc finger domain in a family with digital anomalies.
American journal of medical genetics. Part A
2017
Abstract
Mutations in GLI3, which encodes a transcription factor of the Hedgehog signaling pathway, cause several developmental anomalies linked to inappropriate tissue patterning. Here, we report a novel missense variant in the fifth zinc finger domain of GLI3 (c.1826G>A; p.(Cys609Tyr)) initially identified in a proband with preaxial polydactyly type IV, developmental delay, sensorineural hearing loss, skeletal, and genitourinary anomalies. Additional family members exhibited various digital anomalies such as preaxial polydactyly, syndactyly, and postaxial polydactyly either in isolation or combined. Functional studies of Cys609Tyr GLI3 in cultured cells showed abnormal GLI3 processing leading to decreased GLI3 repressor production, increased basal transcriptional activity, and submaximal GLI reporter activity with Hedgehog pathway activation, thus demonstrating an intriguing molecular mechanism for this GLI3-related phenotype. Given the complexity of GLI3 post-translational processing and opposing biological functions as a transcriptional activator and repressor, our findings highlight the importance of performing functional studies of presumed GLI3 variants. This family also demonstrates how GLI3 variants are variably expressed.
View details for PubMedID 28884880
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FOXP1-related intellectual disability syndrome: a recognisable entity.
Journal of medical genetics
2017; 54 (9): 613–23
Abstract
Mutations in forkhead box protein P1 (FOXP1) cause intellectual disability (ID) and specific language impairment (SLI), with or without autistic features (MIM: 613670). Despite multiple case reports no specific phenotype emerged so far.We correlate clinical and molecular data of 25 novel and 23 previously reported patients with FOXP1 defects. We evaluated FOXP1 activity by an in vitro luciferase model and assessed protein stability in vitro by western blotting.Patients show ID, SLI, neuromotor delay (NMD) and recurrent facial features including a high broad forehead, bent downslanting palpebral fissures, ptosis and/or blepharophimosis and a bulbous nasal tip. Behavioural problems and autistic features are common. Brain, cardiac and urogenital malformations can be associated. More severe ID and NMD, sensorineural hearing loss and feeding difficulties are more common in patients with interstitial 3p deletions (14 patients) versus patients with monogenic FOXP1 defects (34 patients). Mutations result in impaired transcriptional repression and/or reduced protein stability.FOXP1-related ID syndrome is a recognisable entity with a wide clinical spectrum and frequent systemic involvement. Our data will be helpful to evaluate genotype-phenotype correlations when interpreting next-generation sequencing data obtained in patients with ID and/or SLI and will guide clinical management.
View details for PubMedID 28735298
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Germline Loss-of-Function Mutations in EPHB4 Cause a Second Form of Capillary Malformation-Arteriovenous Malformation (CM-AVM2) Deregulating RAS-MAPK Signaling.
Circulation
2017
Abstract
Background -Most AVMs are localized and occur sporadically; however they also can be multifocal in autosomal dominant disorders, such as Hereditary Hemorrhagic Telangiectasia (HHT) and Capillary Malformation-Arteriovenous Malformation (CM-AVM). Previously, we identified RASA1 mutations in 50% of patients with CM-AVM. Herein we studied non-RASA1 patients to further elucidate the pathogenicity of CMs and AVMs. Methods -We conducted a genome-wide linkage study on a CM-AVM family. Whole exome sequencing was also performed on 9 unrelated CM-AVM families. We identified a candidate-gene and screened it in a large series of patients. The influence of several missense variants on protein function was also studied in vitroResults -We found evidence for linkage in two loci. Whole-exome sequencing data unraveled four distinct damaging variants in EPHB4 in five families that co-segregated with CM-AVM. Overall, screening of EPHB4 detected 47 distinct mutations in 54 index patients: 27 lead to a premature stop codon or splice-site alteration, suggesting loss of function. The other 20 are non-synonymous variants that result in amino-acid substitutions. In vitro expression of several mutations confirmed loss of function of EPHB4. The clinical features included multifocal CMs, telangiectasias, and AVMs. Conclusions -We found EPHB4 mutations in patients with multifocal CMs associated with AVMs. The phenotype, CM-AVM2, mimics RASA1-related CM-AVM1 and also HHT. RASA1 encoded p120RASGAP is a direct effector of EPHB4. Our data highlights the pathogenetic importance of this interaction and indicts EPHB4-RAS-ERK signaling pathway as a major cause for arterio-venous malformations.
View details for PubMedID 28687708
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Recommendations for the integration of genomics into clinical practice
GENETICS IN MEDICINE
2016; 18 (11): 1075-1084
Abstract
The introduction of diagnostic clinical genome and exome sequencing (CGES) is changing the scope of practice for clinical geneticists. Many large institutions are making a significant investment in infrastructure and technology, allowing clinicians to access CGES, especially as health-care coverage begins to extend to clinically indicated genomic sequencing-based tests. Translating and realizing the comprehensive clinical benefits of genomic medicine remain a key challenge for the current and future care of patients. With the increasing application of CGES, it is necessary for geneticists and other health-care providers to understand its benefits and limitations in order to interpret the clinical relevance of genomic variants identified in the context of health and disease. New, collaborative working relationships with specialists across diverse disciplines (e.g., clinicians, laboratorians, bioinformaticians) will undoubtedly be key attributes of the future practice of clinical genetics and may serve as an example for other specialties in medicine. These new skills and relationships will also inform the development of the future model of clinical genetics training curricula. To address the evolving role of the clinical geneticist in the rapidly changing climate of genomic medicine, two Clinical Genetics Think Tank meetings were held that brought together physicians, laboratorians, scientists, genetic counselors, trainees, and patients with experience in clinical genetics, genetic diagnostics, and genetics education. This article provides recommendations that will guide the integration of genomics into clinical practice.Genet Med advance online publication 12 May 2016Genetics in Medicine (2016); doi:10.1038/gim.2016.17.
View details for DOI 10.1038/gim.2016.17
View details for PubMedID 27171546
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Respiratory System Involvement in Costello Syndrome
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
2016; 170 (7): 1849-1857
Abstract
Costello syndrome (CS) is a multisystem disorder caused by heterozygous germline mutations in the HRAS proto-oncogene. Respiratory system complications have been reported in individuals with CS, but a comprehensive description of the full spectrum and incidence of respiratory symptoms in these patients is not available. Here, we report the clinical course of four CS patients with respiratory complications as a major cause of morbidity. Review of the literature identified 56 CS patients with descriptions of their neonatal course and 17 patients in childhood/adulthood. We found that in the neonatal period, respiratory complications are seen in approximately 78% of patients with transient respiratory distress reported in 45% of neonates. Other more specific respiratory diagnoses were reported in 62% of patients, the majority of which comprised disorders of the upper and lower respiratory tract. Symptoms of upper airway obstruction were reported in CS neonates but were more commonly diagnosed in childhood/adulthood (71%). Analysis of HRAS mutations and their respiratory phenotype revealed that the common p.Gly12Ser mutation is more often associated with transient respiratory distress and other respiratory diagnoses. Respiratory failure and dependence on mechanical ventilation occurs almost exclusively with rare mutations. In cases of prenatally diagnosed CS, the high incidence of respiratory complications in the neonatal period should prompt anticipatory guidance and development of a postnatal management plan. This may be important in cases involving rarer mutations. Furthermore, the high frequency of airway obstruction in CS patients suggests that otorhinolaryngological evaluation and sleep studies should be considered. © 2016 Wiley Periodicals, Inc.
View details for DOI 10.1002/ajmg.a.37655
View details for PubMedID 27102959
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36th Annual David W. Smith Workshop on Malformations and Morphogenesis: Abstracts of the 2015 Annual Meeting
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
2016; 170 (7): 1665-1726
Abstract
The 36th Annual David W Smith Workshop on Malformations and Morphogenesis was held on August 14-19, 2015 at the Harbourtowne Conference Center in St. Michaels Maryland. The Workshop, which honors the legacy of David W Smith, brought together over 120 clinicians and researchers interested in congenital malformations and their underlying mechanisms of morphogenesis. As is the tradition of the meeting, the Workshop highlighted five themes besides mechanisms of morphogenesis: Rasopathies, Eye Malformations, Therapeutics, Prenatal Diagnosis, and Disorders of Sex Development. This Conference Report includes the abstracts presented at the 2015 Workshop. © 2016 Wiley Periodicals, Inc.
View details for DOI 10.1002/ajmg.a.37600
View details for PubMedID 27119594
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Prenatally Diagnosed Cases of Binder Phenotype Complicated by Respiratory Distress in the Immediate Postnatal Period.
Journal of ultrasound in medicine
2016; 35 (6): 1353-1358
Abstract
Binder phenotype, or maxillonasal dysostosis, is a distinctive pattern of facial development characterized by a short nose with a flat nasal bridge, an acute nasolabial angle, a short columella, a convex upper lip, and class III malocclusion. We report 3 cases of prenatally diagnosed Binder phenotype associated with perinatal respiratory impairment.
View details for DOI 10.7863/ultra.15.02050
View details for PubMedID 27162279
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Novel X-linked syndrome of cardiac valvulopathy, keloid scarring, and reduced joint mobility due to filamin A substitution G1576R.
American journal of medical genetics. Part A
2016; 170 (4): 891-895
Abstract
Filamin A (FLNA) is known to be involved in intracellular actin binding, cell migration, scaffolding, and signaling. We report a novel X-linked syndrome characterized by cardiac valvular disease, keloid scarring and reduced joint mobility in male second cousins due to a previously unreported mutation in FLNA. Whole exome sequencing was performed using standard methods and segregation analysis was performed in affected and non-affected family members. A novel hemizygous c.4726G>A (p.G1576R) mutation in FLNA was detected. Segregation analysis performed on multiple maternal family members showed c.4726G>A (p.G1576R) segregated with disease in an X-linked inheritance pattern. The findings in these cases are distinct from previously described FLNA related disorders by virtue of decreased joint mobility and spontaneous keloid scarring. They occur in association with a novel mutation and represent a novel genetic syndrome. © 2015 Wiley Periodicals, Inc.
View details for DOI 10.1002/ajmg.a.37491
View details for PubMedID 26686323
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Patient preferences for prenatal testing of microdeletion and microduplication syndromes
PRENATAL DIAGNOSIS
2016; 36 (3): 244-251
Abstract
To assess pregnant women's preferences regarding prenatal testing for microdeletion and microduplication conditions, and to identify what factors might influence their decisions.A written questionnaire was administered to pregnant women presenting for prenatal ultrasound. The questionnaire described the salient features of six microdeletion and microduplication syndromes of varying penetrance. Women were asked to indicate whether they would choose to test for each condition via an invasive diagnostic procedure, a non-invasive blood test, or not at all. Demographic and obstetrical data were also obtained.One hundred twenty-four women returned the questionnaire (response rate 89.2%). More than half of women (50.8%) made distinctions between conditions, and would choose a mixture of invasive testing, non-invasive testing, and no testing, depending on the condition. Testing preferences differed based on penetrance and features of the conditions. Prior prenatal testing, ethnicity, and education level were significantly associated (p<0.05) with testing decisions.Pregnant women do not perceive all microdeletion and microduplication conditions to be equal, and prenatal testing for such conditions is not always considered an all or none process. A test menu or filtering process may be a more optimal method of offering prenatal testing for microdeletion and microduplication conditions.
View details for DOI 10.1002/pd.4760
View details for Web of Science ID 000372555000007
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A Multifaceted Mentoring Program for Junior Faculty in Academic Pediatrics
TEACHING AND LEARNING IN MEDICINE
2016; 28 (3): 320-328
Abstract
The departure of physician-scientists from education and research into clinical practice is a growing challenge for the future of academic medicine. Junior faculty face competing demands for clinical productivity, teaching, research, and work-life integration, which can undermine confidence in the value of an academic career. Mentorship is important to foster career development and satisfaction in junior faculty.The goals of this academic pediatrics department were to develop, implement, and evaluate a multifaceted pediatric mentoring program to promote retention and satisfaction of junior faculty. Program elements included one-on-one mentor-mentee meetings, didactic workshops, grant review assistance, and facilitated peer-group mentoring. Program effectiveness was assessed using annual surveys of mentees and structured mentee exit interviews, as well as retention data for assistant professors.The mentees were instructors and assistant professors in the department of pediatrics.Seventy-nine mentees participated in the program from 2007 through 2014. The response rate from seven annual surveys was 84%. Sixty-nine percent of mentees felt more prepared to advance their careers, 81% had a better understanding of the criteria for advancement, 84% were satisfied with the program, and 95% found mentors accessible. Mentees who exited the program reported they most valued the one-on-one mentoring and viewed the experience positively regardless of promotion. Retention of assistant professors improved after initiation of the program; four of 13 hired from 2002 to 2006 left the institution, whereas 18 of 18 hired from 2007 to 2014 were retained.This multifaceted mentoring program appeared to bolster satisfaction and enhance retention of junior pediatric faculty. Mentees reported increased understanding of the criteria for promotion and viewed the program as a positive experience regardless of career path. Individual mentor-mentee meetings were needed at least twice yearly to establish the mentoring relationship. Identifying "next steps" at the end of individual meetings was helpful to hold both parties accountable for progress. Mentees most valued workshops fostering development of tangible skills (such as scientific writing) and those clarifying the criteria for promotion more transparent. Facilitated peer-group mentoring for mentees at the instructor rank provided valuable peer support.
View details for DOI 10.1080/10401334.2016.1153476
View details for PubMedID 27054562
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Patient preferences for prenatal testing of microdeletion and microduplication syndromes.
Prenatal diagnosis
2015
Abstract
To assess pregnant women's preferences regarding prenatal testing for microdeletion and microduplication conditions, and to identify what factors might influence their decisions.A written questionnaire was administered to pregnant women presenting for prenatal ultrasound. The questionnaire described the salient features of six microdeletion and microduplication syndromes of varying penetrance. Women were asked to indicate whether they would choose to test for each condition via an invasive diagnostic procedure, a non-invasive blood test, or not at all. Demographic and obstetrical data were also obtained.One hundred twenty-four women returned the questionnaire (response rate 89.2%). More than half of women (50.8%) made distinctions between conditions, and would choose a mixture of invasive testing, non-invasive testing, and no testing, depending on the condition. Testing preferences differed based on penetrance and features of the conditions. Prior prenatal testing, ethnicity, and education level were significantly associated (p<0.05) with testing decisions.Pregnant women do not perceive all microdeletion and microduplication conditions to be equal, and prenatal testing for such conditions is not always considered an all or none process. A test menu or filtering process may be a more optimal method of offering prenatal testing for microdeletion and microduplication conditions.
View details for DOI 10.1002/pd.4760
View details for PubMedID 26687911
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DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies
EUROPEAN JOURNAL OF HUMAN GENETICS
2015; 23 (11): 1473-1481
Abstract
Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A (DYRK1A ) is a highly conserved gene located in the Down syndrome critical region. It has an important role in early development and regulation of neuronal proliferation. Microdeletions of chromosome 21q22.12q22.3 that include DYRK1A (21q22.13) are rare and only a few pathogenic single-nucleotide variants (SNVs) in the DYRK1A gene have been described, so as of yet, the landscape of DYRK1A disruptions and their associated phenotype has not been fully explored. We have identified 14 individuals with de novo heterozygous variants of DYRK1A; five with microdeletions, three with small insertions or deletions (INDELs) and six with deleterious SNVs. The analysis of our cohort and comparison with published cases reveals that phenotypes are consistent among individuals with the 21q22.12q22.3 microdeletion and those with translocation, SNVs, or INDELs within DYRK1A. All individuals shared congenital microcephaly at birth, intellectual disability, developmental delay, severe speech impairment, short stature, and distinct facial features. The severity of the microcephaly varied from -2 SD to -5 SD. Seizures, structural brain abnormalities, eye defects, ataxia/broad-based gait, intrauterine growth restriction, minor skeletal abnormalities, and feeding difficulties were present in two-thirds of all affected individuals. Our study demonstrates that haploinsufficiency of DYRK1A results in a new recognizable syndrome, which should be considered in individuals with Angelman syndrome-like features and distinct facial features. Our report represents the largest cohort of individuals with DYRK1A disruptions to date, and is the first attempt to define consistent genotype-phenotype correlations among subjects with 21q22.13 microdeletions and DYRK1A SNVs or small INDELs.European Journal of Human Genetics advance online publication, 6 May 2015; doi:10.1038/ejhg.2015.71.
View details for DOI 10.1038/ejhg.2015.71
View details for PubMedID 25944381
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Detection Rates for Aneuploidy by First-Trimester and Sequential Screening
OBSTETRICS AND GYNECOLOGY
2015; 126 (4): 752-758
View details for DOI 10.1097/AOG.0000000000001040
View details for Web of Science ID 000369637500010
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Detection Rates for Aneuploidy by First-Trimester and Sequential Screening.
Obstetrics and gynecology
2015; 126 (4): 753-759
Abstract
To estimate detection rates for aneuploidy by first-trimester and sequential screening.The study included women with singleton pregnancies who participated in the California Prenatal Screening Program with estimated delivery dates from August 2009 to December 2012 who had first- or first- and second-trimester (sequential) screening. Detection rates were measured for target (trisomies 21 and 18) and other aneuploidies identified from the California Chromosome Defect Registry.Of 452,901 women screened, 17,435 (3.8%) were screen-positive for Down syndrome only; 433 (0.1%) for trisomy 18 only; 1,689 (0.4%) for both Down syndrome and trisomy 18; and 2,947 (0.7%) for neural tube defects, Smith-Lemli-Opitz syndrome, or for multiple conditions. The detection rates were Down syndrome-92.9% (95% confidence interval [CI] 91.4-94.2); trisomy 18-93.2% (95% CI 90.5-95.9); trisomy 13-80.4% (95% CI 73.9-86.9); 45,X-80.1% (95% CI 73.9-86.3), and triploidy-91.0% (95% CI 84.2-97.9). Overall, the detection rate for chromosome abnormalities was 81.6% (95% CI 80.0-83.1) at an overall false-positive rate of 4.5%.First-trimester and sequential screening are sensitive and specific for the broad range of karyotype abnormalities seen in the population.II.
View details for DOI 10.1097/AOG.0000000000001040
View details for PubMedID 26348180
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Knowledge, understanding, and uptake of noninvasive prenatal testing among Latina women
PRENATAL DIAGNOSIS
2015; 35 (8): 748-753
Abstract
Assess Latina patient understanding of NIPT and identify what factors influence uptake/refusal of NIPT to adapt counseling to the needs and interests of this population.Mixed-methods survey in English and Spanish administered to pregnant Latina patients throughout pregnancy.Sixty-three women participated in our study (67% response rate). 34.9% chose to do NIPT and 65.1% declined. Approximately half of participants (44%) had an NIPT knowledge score of ≤3 out of 6 total questions. Two of the most significant factors influencing uptake of NIPT were a higher reported education level (p=0.015) and a higher NIPT knowledge score (p=0.014). 42.9% of participants knew that NIPT only screens for certain chromosomal conditions. 39% of women who declined NIPT would never consider NIPT in the future.One third of Latina women elected NIPT; a higher reported education level and language were most predictive of this choice. Overall knowledge was significantly lower for women who declined NIPT. Lower knowledge may suggest that not all women are making informed decisions due to varying degrees of informed consent. Providing culturally tailored information can help women navigate the complexities of prenatal testing in order to make decisions most aligned with their values. This article is protected by copyright. All rights reserved.
View details for DOI 10.1002/pd.4599
View details for Web of Science ID 000359024300004
View details for PubMedID 25846645
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ClinGen - The Clinical Genome Resource
NEW ENGLAND JOURNAL OF MEDICINE
2015; 372 (23): 2235-2242
View details for DOI 10.1056/NEJMsr1406261
View details for PubMedID 26014595
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Genomics in the clinic: ethical and policy challenges in clinical next-generation sequencing programs at early adopter USA institutions.
Personalized medicine
2015; 12 (3): 269-282
Abstract
Next-generation sequencing (NGS) technologies are poised to revolutionize clinical diagnosis and treatment, but raise significant ethical and policy challenges. This review examines NGS program challenges through a synthesis of published literature, website and conference presentation content, and interviews at early-adopting institutions in the USA. Institutions are proactively addressing policy challenges related to the management and technical aspects of program development. However, ethical challenges related to patient-related aspects have not been fully addressed. These complex challenges present opportunities to develop comprehensive and standardized regulations across programs. Understanding the strengths, weaknesses and current practices of evolving NGS program approaches are important considerations for institutions developing NGS services, policymakers regulating or funding NGS programs and physicians and patients considering NGS services.
View details for DOI 10.2217/pme.14.88
View details for PubMedID 29771644
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Neonatal Pulmonary Arterial Hypertension and Noonan Syndrome: Two Fatal Cases with a Specific RAF1 Mutation
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
2015; 167A (4): 882-885
Abstract
Mutations in RAF1 are associated with Noonan syndrome and hypertrophic cardiomyopathy. We present two infants with Noonan syndrome and an identical RAF1 mutation, p.Ser257Leu (c.770C>T), who developed severe pulmonary arterial hypertension (PAH) that proved to be fatal. The RAF1 gene encodes Raf-1 kinase, part of the Ras/mitogen-activated kinase (MAPK) signaling pathway, which has been linked to the development of PAH. This specific mutation has been associated with dephosphorylation of a critical serine residue and constitutive activation of the Raf-1 kinase. These two cases suggest that abnormal activation of the Ras/MAPK pathway may play a significant role in the development of pulmonary vascular disease in the subset of patients with Noonan syndrome and a specific RAF1 mutation. © 2015 Wiley Periodicals, Inc.
View details for DOI 10.1002/ajmg.a.37024
View details for Web of Science ID 000352019000035
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De Novo Nonsense Mutations in KAT6A, a Lysine Acetyl-Transferase Gene, Cause a Syndrome Including Microcephaly and Global Developmental Delay.
American journal of human genetics
2015; 96 (3): 498-506
Abstract
Chromatin remodeling through histone acetyltransferase (HAT) and histone deactylase (HDAC) enzymes affects fundamental cellular processes including the cell-cycle, cell differentiation, metabolism, and apoptosis. Nonsense mutations in genes that are involved in histone acetylation and deacetylation result in multiple congenital anomalies with most individuals displaying significant developmental delay, microcephaly and dysmorphism. Here, we report a syndrome caused by de novo heterozygous nonsense mutations in KAT6A (a.k.a., MOZ, MYST3) identified by clinical exome sequencing (CES) in four independent families. The same de novo nonsense mutation (c.3385C>T [p.Arg1129(∗)]) was observed in three individuals, and the fourth individual had a nearby de novo nonsense mutation (c.3070C>T [p.Arg1024(∗)]). Neither of these variants was present in 1,815 in-house exomes or in public databases. Common features among all four probands include primary microcephaly, global developmental delay including profound speech delay, and craniofacial dysmorphism, as well as more varied features such as feeding difficulties, cardiac defects, and ocular anomalies. We further demonstrate that KAT6A mutations result in dysregulation of H3K9 and H3K18 acetylation and altered P53 signaling. Through histone and non-histone acetylation, KAT6A affects multiple cellular processes and illustrates the complex role of acetylation in regulating development and disease.
View details for DOI 10.1016/j.ajhg.2015.01.017
View details for PubMedID 25728775
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Exome Sequencing for the Diagnosis of 46,XY Disorders of Sex Development.
journal of clinical endocrinology and metabolism
2015; 100 (2): E333-44
View details for DOI 10.1210/jc.2014-2605
View details for PubMedID 25383892
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Increased body mass in infancy and early toddlerhood in Angelman syndrome patients with uniparental disomy and imprinting center defects.
American journal of medical genetics. Part A
2015; 167A (1): 142-146
Abstract
The diagnosis of Angelman syndrome (AS) is based on clinical features and genetic testing. Developmental delay, severe speech impairment, ataxia, atypical behavior and microcephaly by two years of age are typical. Feeding difficulties in young infants and obesity in late childhood can also be seen. The NIH Angelman-Rett-Prader-Willi Consortium and others have documented genotype-phenotype associations including an increased body mass index in children with uniparental disomy (UPD) or imprinting center (IC) defects. We recently encountered four cases of infantile obesity in non-deletion AS cases, and therefore examined body mass measures in a cohort of non-deletion AS cases. We report on 16 infants and toddlers (ages 6 to 44 months; 6 female, and 10 male) with severe developmental delay. Birth weights were appropriate for gestational age in most cases, >97th% in one case and not available in four cases. The molecular subclass case distribution consisted of: UPD (n = 2), IC defect (n = 3), UPD or IC defect (n = 3), and UBE3A mutation (n = 8). Almost all (7 out of 8) UPD, IC and UPD/IC cases went on to exhibit >90th% age- and gender-appropriate weight for height or BMI within the first 44 months. In contrast, no UBE3A mutation cases exhibited obesity or pre-obesity measures (percentiles ranged from <3% to 55%). These findings demonstrate that increased body mass may be evident as early as the first year of life and highlight the utility of considering the diagnosis of AS in the obese infant or toddler with developmental delay, especially when severe. Although a mechanism explaining the association of UPD, and IC defects with obesity has not been identified, recognition of this correlation may inform investigation of imprinting at the PWS/AS locus and obesity. © 2014 Wiley Periodicals, Inc.
View details for DOI 10.1002/ajmg.a.36831
View details for PubMedID 25402239
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Increased body mass in infancy and early toddlerhood in Angelman syndrome patients with uniparental disomy and imprinting center defects.
American journal of medical genetics. Part A
2015; 167 (1): 142-146
View details for DOI 10.1002/ajmg.a.36831
View details for PubMedID 25402239
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Genomics in the clinic: ethical and policy challenges in clinical next-generation sequencing programs at early adopter USA institutions
PERSONALIZED MEDICINE
2015; 12 (3): 269-282
View details for DOI 10.2217/PME.14.88
View details for Web of Science ID 000355751600011
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Perinatal Features of the RASopathies: Noonan Syndrome, Cardiofaciocutaneous Syndrome and Costello Syndrome
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
2014; 164A (11): 2814-2821
Abstract
The RASopathies are a family of developmental disorders caused by heritable defects of the RAS/MAPK signaling pathway. While the postnatal presentation of this group of disorders is well known, the prenatal and neonatal findings are less widely recognized. We report on the perinatal presentation of 10 patients with Noonan syndrome (NS), nine with Cardiofaciocutaneous syndrome (CFCS) and three with Costello syndrome (CS), in conjunction with the results of a comprehensive literature review. The majority of perinatal findings in NS, CS, and CFCS are shared: polyhydramnios; prematurity; lymphatic dysplasia; macrosomia; relative macrocephaly; respiratory distress; hypotonia, as well as cardiac and renal anomalies. In contrast, fetal arrhythmia and neonatal hypoglycemia are relatively specific to CS. NS, CS, and CFCS should all be considered as a possible diagnosis in pregnancies with a normal karyotype and ultrasound findings of a RASopathy. Recognition of the common perinatal findings of these disorders should facilitate both their prenatal and neonatal diagnosis. © 2014 Wiley Periodicals, Inc.
View details for DOI 10.1002/ajmg.a.36737
View details for Web of Science ID 000344187200019
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Attitudes of mothers of children with down syndrome towards noninvasive prenatal testing.
Journal of genetic counseling
2014; 23 (5): 805-813
Abstract
Noninvasive prenatal testing (NIPT) allows for highly sensitive detection of Down syndrome early in pregnancy with no risk of miscarriage, therefore potentially increasing the number of pregnancies identified with Down syndrome. This study assesses how mothers of children with Down syndrome perceive NIPT, especially the impact they think it will have on their families and other families with children who have Down syndrome. Seventy-three self-reported mothers of children with Down syndrome responded to an anonymous online survey emailed to, and posted on, message boards of various Down syndrome support groups and networks. Data analysis included chi-square tests and thematic analysis. Fifty-nine percent of respondents indicated they would use NIPT in the future; respondents who had not used prenatal testing in the past were significantly less likely to report interest in using NIPT in the future than those who had prenatal testing previously (p < .001). Many respondents felt NIPT could lead to increased terminations (88 %), increased social stigma (57 %), and decreased availability of services for individuals with Down syndrome (64 %). However, only 16 % believed availability of new noninvasive tests would be the most important factor in determining the number of pregnancies with Down syndrome terminated in the future. Additionally, 48 % believed health care providers give biased or incorrect information about Down syndrome at the time of diagnosis, and 24 % felt this incorrect information leads to terminations of pregnancies affected with Down syndrome. Results suggest although mothers of children with Down syndrome believe new noninvasive testing will lead to an increase in termination of pregnancies with Down syndrome, they do not think it is the MOST important factor. They also highlight the need to provide a diagnosis of Down syndrome in a balanced and objective manner.
View details for DOI 10.1007/s10897-014-9694-7
View details for PubMedID 24481673
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Clinical whole-exome sequencing: are we there yet?
GENETICS IN MEDICINE
2014; 16 (9): 717-719
Abstract
Background:Clinical laboratories began offering whole-exome sequencing in 2011 at a cost between $4,500 and $9,000. Reported detection rates for deleterious mutations range from 25 to 50%. Based on the experience of our clinical genetics service, actual success rates may be lower than estimated rates. We report results from our own experience along with a survey of clinical geneticists to ascertain (i) current success rates for causal gene detection in a clinical setting; (ii) if there are insurance authorization issues; and (iii) if turnaround times quoted by the clinical laboratories are accurate; we also gauge provider opinions toward clinical whole-exome sequencing.Methods:We reviewed our results and the results of a survey that was electronically distributed to 47 clinical genetics centers.Results:A total of 35 exome reports were available. If all positive results are collated, we observe a success rate of 22.8%. One result incorrectly identified a known benign variant as pathogenic. Some insurers covered all testing, whereas others denied any insurance coverage. Only three (23.1%) of our reports were available within the laboratory's quoted turnaround times. More than 50% of clinicians queried in our survey had not ordered whole-exome sequencing at the current time, many stating concerns regarding interpretation, insurance coverage, and cost.Conclusion:Clinical whole-exome sequencing has proven diagnostic utility; however, currently many clinicians have concerns regarding interpretation of results, insurance coverage, and cost.Genet Med advance online publication 13 February 2014Genetics in Medicine (2014); doi:10.1038/gim.2014.10.
View details for DOI 10.1038/gim.2014.10
View details for Web of Science ID 000341830800010
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Nine patients with Xp22.31 microduplication, cognitive deficits, seizures, and talipes anomalies.
American journal of medical genetics. Part A
2014; 164A (8): 2097-2103
Abstract
Comparative genomic hybridization (CGH) arrays have significantly changed the approach to identifying genetic alterations causing intellectual disability and congenital anomalies. Several studies have described the microduplication of Xp22.31, involving the STS gene. In such reports characteristic features and pathogenicity of Xp22.31 duplications remains a subject of debate. Here we present a series of nine previously unreported individuals with Xp22.31 duplications, found through microarray analysis in the course of genetic workup for developmental delay, associated with a combination of talipes anomalies, seizures and/or feeding difficulties. The size of the Xp22.31 duplications ranged from 294 kb to 1.6 Mb. We show a comparison of the breakpoints, inheritance and clinical phenotype, and a review of the literature. This clinically detailed series of Xp22.31 duplication patients provides evidence that the Xp22.31 duplication contributes to a common phenotype. © 2014 Wiley Periodicals, Inc.
View details for DOI 10.1002/ajmg.a.36598
View details for PubMedID 24800990
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Nine patients with Xp22.31 microduplication, cognitive deficits, seizures, and talipes anomalies.
American journal of medical genetics. Part A
2014; 164 (8): 2097-2103
View details for DOI 10.1002/ajmg.a.36598
View details for PubMedID 24800990
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Noninvasive prenatal diagnosis in a fetus at risk for methylmalonic acidemia.
Genetics in medicine
2014; 16 (7): 564-567
Abstract
Purpose:Prenatal diagnosis of fetal Mendelian disorders can benefit from noninvasive approaches using fetal cell-free DNA in maternal plasma. Detecting metabolic disorders before birth can result in immediate treatment postpartum in order to optimize outcome.Methods:We developed a mathematical model and an experimental methodology to analyze the case of a fetus with a 25% risk of inheriting two known mutations in MUT that cause methylmalonic acidemia. To accomplish this, we measured allelic counts at the mutation sites and the fetal fraction from high minor-allele-frequency single-nucleotide polymorphism positions.Results:By counting linked alleles, the test was able to distinguish 11 positive markers from the negative controls and thereby determine whether or not the mutations carried by the parents were inherited by the fetus. For a homozygous fetus, the Z-score of the mutation site was 5.97, whereas the median Z-score of all the linked alleles was 4.56 when all negative (heterozygous) controls had a Z-score <2.5.Conclusion:The application of this methodology for diagnosing methylmalonic acidemia shows that this is a cost-effective and noninvasive approach to diagnosing known mutations related to Mendelian disorders in the fetus.Genet Med advance online publication 9 January 2014Genetics in Medicine (2014); doi:10.1038/gim.2013.194.
View details for DOI 10.1038/gim.2013.194
View details for PubMedID 24406457
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Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance
HUMAN MOLECULAR GENETICS
2014; 23 (11): 2888-2900
Abstract
Cornelia de Lange syndrome (CdLS) is a multisystem genetic disorder with distinct facies, growth failure, intellectual disability, distal limb anomalies, gastrointestinal and neurological disease. Mutations in NIPBL, encoding a cohesin regulatory protein, account for more than 80% of cases with typical facies. Mutations in the core cohesin complex proteins, encoded by the SMC1A, SMC3 and RAD21 genes, together account for ∼5% of subjects, often with atypical CdLS features. Recently, we identified mutations in the X-linked gene HDAC8 as the cause of a small number of CdLS cases. Here we report a cohort of 35 individuals with an emerging spectrum of features caused by HDAC8 mutations. For several individuals, the diagnosis of CdLS was not considered prior to genomic testing. Most mutations identified are missense and de novo. Many cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA. We also identified eight hemizygous males who are more severely affected. The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features. HDAC8 encodes the lysine deacetylase for the cohesin subunit SMC3 and analysis of the functional consequences of the missense mutations indicates that all cause a loss of enzymatic function. These data demonstrate that loss of function mutations in HDAC8 cause a range of overlapping human developmental phenotypes, including a phenotypically distinct subgroup of CdLS.
View details for DOI 10.1093/hmg/ddu002
View details for Web of Science ID 000336483200008
View details for PubMedID 24403048
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NIPT in a Clinical Setting: An analysis of Uptake in the First Months of Clinical Availability.
Journal of genetic counseling
2014; 23 (1): 72-78
Abstract
The objective of our study was to describe the clinical experience in offering noninvasive prenatal testing (NIPT) for aneuploidy to pregnant patients, highlighting the clinical utility, barriers to acceptance and limitations of this novel test. Data were collected from 961 patients offered NIPT from 3/1/12 to 9/30/12. Univariate and multivariate logistic regression analysis was performed. Twenty-eight percent of patients elected NIPT and 72 % declined. Women continue to elect less sensitive and less specific screening through biochemical markers and nuchal translucency. Women considering all options at average risk for aneuploidy were less likely to accept NIPT testing than women who had a risk adjustment from an ultrasound marker or routine screening test. In our multi-ethnic population, Filipina women were significantly less likely to elect NIPT compared to other ethnicities. Five percent of NIPT ordered failed analysis. Several chromosome abnormalities were detected through CVS or amniocentesis that would not have been detected by NIPT. Even though NIPT offers a non-invasive, highly sensitive and specific analysis for aneuploidy, the majority of women in our study declined this option. NIPT should be offered in the context of genetic counseling so that women understand the limitations of the testing and make an educated decision about the testing option best suited to their situation.
View details for DOI 10.1007/s10897-013-9609-z
View details for PubMedID 23723049
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Expansion of the TARP syndrome phenotype associated with de novo mutations and mosaicism.
American journal of medical genetics. Part A
2014; 164A (1): 120-128
Abstract
The TARP syndrome (Talipes equinovarus, Atrial septal defect, Robin sequence, and Persistent left superior vena cava) is an X-linked disorder that was determined to be caused by mutations in RBM10 in two families, and confirmed in a subsequent case report. The first two original families were quite similar in phenotype, with uniform early lethality although a confirmatory case report showed survival into childhood. Here we report on five affecteds from three newly recognized families, including patients with atypical manifestations. None of the five patients had talipes and others also lacked cardinal TARP features of Robin sequence and atrial septal defect. All three families demonstrated de novo mutations, and one of the families had two recurrences, with demonstrable maternal mosaicism. © 2013 Wiley Periodicals, Inc.
View details for DOI 10.1002/ajmg.a.36212
View details for PubMedID 24259342
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Whole-Exome/Genome Sequencing and Genomics
PEDIATRICS
2013; 132: S211-S215
Abstract
As medical genetics has progressed from a descriptive entity to one focused on the functional relationship between genes and clinical disorders, emphasis has been placed on genomics. Genomics, a subelement of genetics, is the study of the genome, the sum total of all the genes of an organism. The human genome, which is contained in the 23 pairs of nuclear chromosomes and in the mitochondrial DNA of each cell, comprises >6 billion nucleotides of genetic code. There are some 23 000 protein-coding genes, a surprisingly small fraction of the total genetic material, with the remainder composed of noncoding DNA, regulatory sequences, and introns. The Human Genome Project, launched in 1990, produced a draft of the genome in 2001 and then a finished sequence in 2003, on the 50th anniversary of the initial publication of Watson and Crick's paper on the double-helical structure of DNA. Since then, this mass of genetic information has been translated at an ever-increasing pace into useable knowledge applicable to clinical medicine. The recent advent of massively parallel DNA sequencing (also known as shotgun, high-throughput, and next-generation sequencing) has brought whole-genome analysis into the clinic for the first time, and most of the current applications are directed at children with congenital conditions that are undiagnosable by using standard genetic tests for single-gene disorders. Thus, pediatricians must become familiar with this technology, what it can and cannot offer, and its technical and ethical challenges. Here, we address the concepts of human genomic analysis and its clinical applicability for primary care providers.
View details for DOI 10.1542/peds.2013-1032E
View details for Web of Science ID 000329164700003
View details for PubMedID 24298129
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The Decision to Continue a Pregnancy Affected by Down Syndrome: Timing of Decision and Satisfaction with Receiving a Prenatal Diagnosis
JOURNAL OF GENETIC COUNSELING
2013; 22 (5): 587-593
Abstract
In order to provide the best genetic counseling possible for women who learn of a diagnosis of Down syndrome prenatally, we sought to assess the timing of the decision to continue a pregnancy and the satisfaction these women had with learning this information. Fifty-six mothers of children with Down syndrome diagnosed prenatally between 2007 and 2010 completed a survey regarding their experience with decision-making after prenatal diagnosis. Approximately one third (17/56) of participants reported they knew before getting pregnant that they would not terminate for any reason, and almost half of the participants (24/56) reported they did not decide to continue their pregnancy until after the diagnosis. Many participants (82 %; 42/56) stated that learning the diagnosis during pregnancy increased their anxiety. The majority (88 %; 45/56) also reported that if they could do it over again, they would undergo prenatal testing for preparation purposes, despite increased anxiety. Religious and spiritual beliefs as well as feeling attached to the baby were the personal factors that had the greatest impact on most women's decision-making. Despite increased anxiety caused by learning the diagnosis prenatally, most women favored prenatal diagnosis as it allowed them time to process the information and prepare for the birth of their child.
View details for DOI 10.1007/s10897-013-9590-6
View details for Web of Science ID 000324496300004
View details for PubMedID 23604903
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Best ethical practices for clinicians and laboratories in the provision of noninvasive prenatal testing.
Prenatal diagnosis
2013; 33 (7): 656-661
Abstract
OBJECTIVE: The goal of this study is to provide an ethical framework for clinicians and companies providing noninvasive prenatal testing using cell-free fetal DNA or whole fetal cells. METHOD: In collaboration with a National Institutes of Health-supported research ethics consultation committee together with feedback from an interdisciplinary group of clinicians, members of industry, legal experts, and genetic counselors, we developed a set of best practices for the provision of noninvasive prenatal genetic testing. RESULTS: Principal recommendations include the amendment of current informed consent procedures to include attention to the noninvasive nature of new testing and the potential for a broader range of results earlier in the pregnancy. We strongly recommend that tests should only be provided through licensed medical providers and not directly to consumers. CONCLUSION: Prenatal tests, including new methods using cell-free fetal DNA, are not currently regulated by government agencies, and limited professional guidance is available. In the absence of regulation, companies and clinicians should cooperate to adopt responsible best ethical practices in the provision of these tests. © 2013 John Wiley & Sons, Ltd.
View details for DOI 10.1002/pd.4144
View details for PubMedID 23613322
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Expanding the Phenotype of Cardiovascular Malformations in Adams-Oliver Syndrome
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
2013; 161A (6): 1386-1389
Abstract
We describe a newborn with a phenotype consistent with Adams-Oliver syndrome and truncus arteriosus. Although cardiovascular malformations associated with this syndrome have been previously published in the literature, this is the first description of truncus arteriosus in a patient with Adams-Oliver syndrome. We review other reports of Adams-Oliver syndrome previously described with cardiovascular malformations, consider possible genetic and embryologic mechanisms, and emphasize the need for cardiology consultation when a diagnosis of Adams-Oliver syndrome is suspected in the differential diagnosis. © 2013 Wiley Periodicals, Inc.
View details for DOI 10.1002/ajmg.a.35864
View details for Web of Science ID 000320649700021
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Expanding the phenotype of cardiovascular malformations in Adams-Oliver syndrome.
American journal of medical genetics. Part A
2013; 161 (6): 1386-9
Abstract
We describe a newborn with a phenotype consistent with Adams-Oliver syndrome and truncus arteriosus. Although cardiovascular malformations associated with this syndrome have been previously published in the literature, this is the first description of truncus arteriosus in a patient with Adams-Oliver syndrome. We review other reports of Adams-Oliver syndrome previously described with cardiovascular malformations, consider possible genetic and embryologic mechanisms, and emphasize the need for cardiology consultation when a diagnosis of Adams-Oliver syndrome is suspected in the differential diagnosis. © 2013 Wiley Periodicals, Inc.
View details for DOI 10.1002/ajmg.a.35864
View details for PubMedID 23613382
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Variables Influencing Pregnancy Termination Following Prenatal Diagnosis of Fetal Chromosome Abnormalities
JOURNAL OF GENETIC COUNSELING
2013; 22 (2): 238-248
Abstract
The objective of this study was to identify variables that may influence the decision to terminate or continue a pregnancy affected by a chromosome abnormality. We performed a retrospective cohort analysis of 286 pregnancies diagnosed with a chromosome abnormality following genetic counseling and prenatal diagnosis. Data obtained included procedure type, chromosome results, ethnicity, maternal age, use of fertility treatments, and uptake of genetic counseling after results, among other factors. Wilcoxon rank sum test, Fisher's exact test, and univariate and multivariate logistic regression models were used for data analysis. The overall termination rate in this study was 82.9 %. A lower likelihood to terminate was found in pregnancies with a diagnosis of a sex chromosome abnormality (OR 0.05, p < .0001), Filipina race (OR 0.10, p = .03), and uptake of second genetic counseling session (OR 0.05, p < .0001). Prior history of termination was associated with increased likelihood to terminate (OR 8.6, p = .02). Factors revealing no statistically significant association with termination included maternal age, gestational age, clinic site, fetal gender, ultrasound anomalies, reason for referral and who informed the patient. Our data affirm the complexity of the decision making process and reinforce that providers should refrain from making assumptions regarding a patient's likelihood to terminate based on factors such as maternal age, gestational age, type of procedure, or ultrasound.
View details for DOI 10.1007/s10897-012-9539-1
View details for Web of Science ID 000316291100008
View details for PubMedID 23001505
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Mutations in FKBP10, which result in Bruck syndrome and recessive forms of osteogenesis imperfecta, inhibit the hydroxylation of telopeptide lysines in bone collagen
HUMAN MOLECULAR GENETICS
2013; 22 (1): 1-17
Abstract
Although biallelic mutations in non-collagen genes account for <10% of individuals with osteogenesis imperfecta, the characterization of these genes has identified new pathways and potential interventions that could benefit even those with mutations in type I collagen genes. We identified mutations in FKBP10, which encodes the 65 kDa prolyl cis-trans isomerase, FKBP65, in 38 members of 21 families with OI. These include 10 families from the Samoan Islands who share a founder mutation. Of the mutations, three are missense; the remainder either introduce premature termination codons or create frameshifts both of which result in mRNA instability. In four families missense mutations result in loss of most of the protein. The clinical effects of these mutations are short stature, a high incidence of joint contractures at birth and progressive scoliosis and fractures, but there is remarkable variability in phenotype even within families. The loss of the activity of FKBP65 has several effects: type I procollagen secretion is slightly delayed, the stabilization of the intact trimer is incomplete and there is diminished hydroxylation of the telopeptide lysyl residues involved in intermolecular cross-link formation in bone. The phenotype overlaps with that seen with mutations in PLOD2 (Bruck syndrome II), which encodes LH2, the enzyme that hydroxylates the telopeptide lysyl residues. These findings define a set of genes, FKBP10, PLOD2 and SERPINH1, that act during procollagen maturation to contribute to molecular stability and post-translational modification of type I procollagen, without which bone mass and quality are abnormal and fractures and contractures result.
View details for DOI 10.1093/hmg/dds371
View details for Web of Science ID 000312643400001
View details for PubMedID 22949511
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Uptake of cell free fetal DNA testing in women with positive serum screening
33rd Annual Pregnancy Meeting of the Society-for-Maternal-Fetal-Medicine (SMFM)
MOSBY-ELSEVIER. 2013: S256–S256
View details for Web of Science ID 000313393500598
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ARTHROGRYPOSIS, RENAL DYSFUNCTION AND CHOLESTASIS (ARC) SYNDROME: A NEW PATIENT CASE REPORT
Western Regional Meeting of the American-Federation-for-Medical-Research
LIPPINCOTT WILLIAMS & WILKINS. 2013: 188–88
View details for Web of Science ID 000312657900279
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Conservatively Managed Fetal Goiter: An Alternative to in utero Therapy.
Fetal diagnosis and therapy
2013; 34 (3): 184-187
Abstract
Fetal goiter may arise from a variety of etiologies including iodine deficiency, overtreatment of maternal Graves' disease, inappropriate maternal thyroid replacement and, rarely, congenital hypothyroidism. Fetal goiter is often associated with a retroflexed neck and polyhydramnios, raising concerns regarding airway obstruction in such cases. Prior reports have advocated for cordocentesis and intra-amniotic thyroid hormone therapy in order to confirm the diagnosis of fetal thyroid dysfunction, reduce the size of the fetal goiter, reduce polyhydramnios, aid with the assistance of maternal thyroid hormone therapy and reduce fetal malpresentation. We report two cases of conservatively managed fetal goiter, one resulting in a vaginal delivery, and no evidence of postnatal respiratory distress despite the presence of polyhydramnios and a retroflexed neck on prenatal ultrasound. © 2013 S. Karger AG, Basel.
View details for DOI 10.1159/000353387
View details for PubMedID 23920148
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Evidence that personal genome testing enhances student learning in a course on genomics and personalized medicine.
PloS one
2013; 8 (7)
Abstract
An emerging debate in academic medical centers is not about the need for providing trainees with fundamental education on genomics, but rather the most effective educational models that should be deployed. At Stanford School of Medicine, a novel hands-on genomics course was developed in 2010 that provided students the option to undergo personal genome testing as part of the course curriculum. We hypothesized that use of personal genome testing in the classroom would enhance the learning experience of students. No data currently exist on how such methods impact student learning; thus, we surveyed students before and after the course to determine its impact. We analyzed responses using paired statistics from the 31 medical and graduate students who completed both pre-course and post-course surveys. Participants were stratified by those who did (N = 23) or did not (N = 8) undergo personal genome testing. In reflecting on the experience, 83% of students who underwent testing stated that they were pleased with their decision compared to 12.5% of students who decided against testing (P = 0.00058). Seventy percent of those who underwent personal genome testing self-reported a better understanding of human genetics on the basis of having undergone testing. Further, students who underwent personal genome testing demonstrated an average 31% increase in pre- to post-course scores on knowledge questions (P = 3.5×10(-6)); this was significantly higher (P = 0.003) than students who did not undergo testing, who showed a non-significant improvement. Undergoing personal genome testing and using personal genotype data in the classroom enhanced students' self-reported and assessed knowledge of genomics, and did not appear to cause significant anxiety. At least for self-selected students, the incorporation of personal genome testing can be an effective educational tool to teach important concepts of clinical genomic testing.
View details for DOI 10.1371/journal.pone.0068853
View details for PubMedID 23935898
View details for PubMedCentralID PMC3720862
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Utilization of available prenatal screening and diagnosis: effects of the California screen program
JOURNAL OF PERINATOLOGY
2012; 32 (12): 907-912
Abstract
In 2009, the California Genetic Disease Branch introduced an aneuploidy screening program allowing Medi-Cal (state insured) patients access to state-sponsored first-trimester screening. The objective of this study was to assess the effect of greater access to prenatal screening on available resources at a single center.Data of prenatal screening and diagnostic procedures performed 4 months before the introduction of the program were compared with those of 12 months following the introduction.Between December 2008 and March 2010, 7689 women underwent first trimester screening, 1286 underwent amniocentesis and 398 underwent chorionic villus sampling. When a comparison was made between the 4 months before and the 12 months after the program's introduction, a greater number of nuchal translucency (NT) examinations was seen to have been performed (384 per month vs 513 per month, P=0.001). Prenatal diagnostic procedures did not increase, but a greater proportion was performed for positive screen results.Introduction of the California screening program was associated with increased NT procedures and fewer invasive procedures for advanced maternal age.
View details for DOI 10.1038/jp.2012.8
View details for Web of Science ID 000311831700002
View details for PubMedID 22402484
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Report of Two Patients and Further Characterization of Interstitial 9p13 Deletion-A Rare But Recurrent Microdeletion Syndrome?
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
2012; 158A (9): 2328-2335
Abstract
To date, an interstitial deletion of 9p13 has been described only two times in the medical literature. These reports were based on routine chromosomal analysis. We report on two additional patients with an interstitial deletion of 9p13 further defined on array CGH who share clinical features with the other two patients previously described. Our first patient is a 16-year-old girl with a 5.9 Mb deletion at 9p13.3-9p13.1, initially detected on routine karyotype analysis and further characterized on array CGH. Our second patient is a 7½-year-old boy with a 4.8 Mb deletion also at 9p13.3-9p13.1. Patients with 9p13 deletion appear to have mild to moderate developmental delay, social and interactive personality, behavior issues such as attention deficit-hyperactivity disorder, short stature, prominent antihelices, hypoplastic nails, and precocious/early puberty. Our 16-year-old patient is the oldest patient described thus far. This report further characterizes this condition and helps to delineate the long-term prognosis in these patients.
View details for DOI 10.1002/ajmg.a.35536
View details for Web of Science ID 000310068700037
View details for PubMedID 22887577
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Mutation risk associated with paternal and maternal age in a cohort of retinoblastoma survivors
HUMAN GENETICS
2012; 131 (7): 1115-1122
Abstract
Autosomal dominant conditions are known to be associated with advanced paternal age, and it has been suggested that retinoblastoma (Rb) also exhibits a paternal age effect due to the paternal origin of most new germline RB1 mutations. To further our understanding of the association of parental age and risk of de novo germline RB1 mutations, we evaluated the effect of parental age in a cohort of Rb survivors in the United States. A cohort of 262 Rb patients was retrospectively identified at one institution, and telephone interviews were conducted with parents of 160 survivors (65.3%). We classified Rb survivors into three groups: those with unilateral Rb were classified as sporadic if they had no or unknown family history of Rb, those with bilateral Rb were classified as having a de novo germline mutation if they had no or unknown family history of Rb, and those with unilateral or bilateral Rb, who had a family history of Rb, were classified as familial. We built two sets of nested logistic regression models to detect an increased odds of the de novo germline mutation classification related to older parental age compared to sporadic and familial Rb classifications. The modeling strategy evaluated effects of continuous increasing maternal and paternal age and 5-year age increases adjusted for the age of the other parent. Mean maternal ages for survivors classified as having de novo germline mutations and sporadic Rb were similar (28.3 and 28.5, respectively) as were mean paternal ages (31.9 and 31.2, respectively), and all were significantly higher than the weighted general US population means. In contrast, maternal and paternal ages for familial Rb did not differ significantly from the weighted US general population means. Although we noted no significant differences between mean maternal and paternal ages between each of the three Rb classification groups, we found increased odds of a survivor being in the de novo germline mutation group for each 5-year increase in paternal age, but these findings were not statistically significant (de novo vs. sporadic ORs 30-34 = 1.7 [0.7-4], ≥ 35 = 1.3 [0.5-3.3]; de novo vs. familial ORs 30-34 = 2.8 [1.0-8.4], ≥ 35 = 1.6 [0.6-4.6]). Our study suggests a weak paternal age effect for Rb resulting from de novo germline mutations consistent with the paternal origin of most of these mutations.
View details for DOI 10.1007/s00439-011-1126-2
View details for Web of Science ID 000305195400010
View details for PubMedID 22203219
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Consanguinity and the risk of congenital heart disease
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
2012; 158A (5): 1236-1241
Abstract
Consanguineous unions have been associated with an increased susceptibility to various forms of inherited disease. Although consanguinity is known to contribute to recessive diseases, the potential role of consanguinity in certain common birth defects is less clear, particularly since the disease pathophysiology may involve genetic and environmental/epigenetic factors. In this study, we ask whether consanguinity affects one of the most common birth defects, congenital heart disease, and identify areas for further research into these birth defects, since consanguinity may now impact health on a near-global basis. A systematic review of consanguinity in congenital heart disease was performed, focusing on non-syndromic disease, with the methodologies and results from studies of different ethnic populations compared. The risks for congenital heart disease have been assessed and summarized collectively and by individual lesion. The majority of studies support the view that consanguinity increases the prevalence of congenital heart disease, however, the study designs differed dramatically. Only a few (n = 3) population-based studies that controlled for potential sociodemographic confounding were identified, and data on individual cardiac lesions were limited by case numbers. Overall the results suggest that the risk for congenital heart disease is increased in consanguineous unions in the studied populations, principally at first-cousin level and closer, a factor that should be considered in empiric risk estimates in genetic counseling. However, for more precise risk estimates a better understanding of the underlying disease factors is needed.
View details for DOI 10.1002/ajmg.a.35272
View details for Web of Science ID 000303000200043
View details for PubMedID 22488956
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What Is Your Diagnosis? The Diagnosis: Trichorhinophalangeal Syndrome Type I
CUTIS
2012; 89 (2): 56-?
View details for Web of Science ID 000300545400002
View details for PubMedID 22474724
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Microdeletion 9q22.3 syndrome includes metopic craniosynostosis, hydrocephalus, macrosomia, and developmental delay
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
2012; 158A (2): 391-399
Abstract
Basal cell nevus syndrome (BCNS), also known as Gorlin syndrome (OMIM #109400) is a well-described rare autosomal dominant condition due to haploinsufficiency of PTCH1. With the availability of comparative genomic hybridization arrays, increasing numbers of individuals with microdeletions involving this locus are being identified. We present 10 previously unreported individuals with 9q22.3 deletions that include PTCH1. While 7 of the 10 patients (7 females, 3 males) did not meet strict clinical criteria for BCNS at the time of molecular diagnosis, almost all of the patients were too young to exhibit many of the diagnostic features. A number of the patients exhibited metopic craniosynostosis, severe obstructive hydrocephalus, and macrosomia, which are not typically observed in BCNS. All individuals older than a few months of age also had developmental delays and/or intellectual disability. Only facial features typical of BCNS, except in those with prominent midforeheads secondary to metopic craniosynostosis, were shared among the 10 patients. The deletions in these individuals ranged from 352 kb to 20.5 Mb in size, the largest spanning 9q21.33 through 9q31.2. There was significant overlap of the deleted segments among most of the patients. The smallest common regions shared among the deletions were identified in order to localize putative candidate genes that are potentially responsible for each of the non-BCNS features. These were a 929 kb region for metopic craniosynostosis, a 1.08 Mb region for obstructive hydrocephalus, and a 1.84 Mb region for macrosomia. Additional studies are needed to further characterize the candidate genes within these regions.
View details for DOI 10.1002/ajmg.a.34216
View details for PubMedID 22190277
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Noninvasive prenatal diagnosis: pregnant women's interest and expected uptake
PRENATAL DIAGNOSIS
2011; 31 (13): 1292-1299
Abstract
To investigate pregnant women's level of future interest in noninvasive prenatal diagnosis (NIPD) and what factors might affect expected uptake of this testing.Written questionnaires were administered to women in their third trimester.One hundred fourteen women returned the questionnaire (80.9% response rate). Of these, 71.9% reported interest in NIPD, 22.7% were ambivalent, and 5.4% were uninterested. Safety of the fetus was the single most important factor in 75% of women's decisions. Factors associated with increased interest in NIPD included: older age (p = 0.036), higher education (p = 0.013), Caucasian or Asian ethnicity (p = 0.011), and higher likelihood to terminate an affected pregnancy (p = 0.002). Nearly 20% of women reported that they would do whatever their doctor recommended regarding NIPD, and 94.4% of women wished to meet with a genetic counselor at some point to discuss NIPD.The majority of pregnant women report hypothetical interest in NIPD, primarily because of increased safety for the fetus, although a significant minority are uninterested or ambivalent. Discussions with healthcare providers regarding NIPD, and their recommendations, are likely to be an important factor in women's decisions about this testing. As such, adequate discussion of the implications of prenatal diagnostic testing will be critical.
View details for DOI 10.1002/pd.2888
View details for Web of Science ID 000298566900013
View details for PubMedID 22028097
View details for PubMedCentralID PMC3225485
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Ectopia Lentis as the Presenting and Primary Feature in Marfan Syndrome
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
2011; 155A (11): 2661-2668
Abstract
Marfan syndrome (MFS) is a multisystem connective tissue disorder with primary involvement of the ocular, cardiovascular, and skeletal systems. We report on eight patients, all presenting initially with bilateral ectopia lentis (EL) during early childhood. These individuals did not have systemic manifestations of MFS, and did not fulfill the revised Ghent diagnostic criteria. However, all patients had demonstratable, disease-causing missense mutations in the FBN1 gene. Based on molecular results, cardiovascular imaging was recommended and led to the identification of mild aortic root changes in seven of the eight patients. The remaining patient had mitral valve prolapse with a normal appearing thoracic aorta. The findings presented in this paper validate the necessity of FBN1 gene testing in all individuals presenting with isolated EL. As we observed, these individuals are at increased risk of cardiovascular complications. Furthermore, we also noted that the majority of our patient cohort's mutations occurred in the 5' portion of the FBN1 gene, and were found to affect highly conserved cysteine residues, which may indicate a possible genotype-phenotype correlation. We conclude that in patients with isolated features of EL, FBN1 mutation analysis is necessary to aid in providing prompt diagnosis, and to identify patients at risk for potentially life-threatening complications. Additionally, knowledge of the type and location of an FBN1 mutation may be useful in providing further clinical correlation regarding phenotypic progression and appropriate medical management.
View details for DOI 10.1002/ajmg.a.34245
View details for PubMedID 21932315
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Horseshoe Kidney and a Rare TSC2 Variant in Two Unrelated Individuals With Tuberous Sclerosis Complex
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
2011; 155A (10): 2534-2537
Abstract
Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem disorder characterized by abnormalities involving the skin, brain, kidney (angiomyolipomas, cysts), and heart. Horseshoe kidney has not been considered to be a common renal manifestation of TSC but it has been previously reported in two patients with TSC. We report on two unrelated females with typical manifestations of TSC, horseshoe kidney, and an identical variant c.5138G>A in exon 39 (p.Arg1713His) of TSC2 gene. These cases provide evidence that horseshoe kidney is associated with TSC and add to the evidence for the pathogenicity of this variant. Furthermore, one of the patients also had a diaphragmatic hernia which has been reported twice in the medical literature in individuals with TSC. It is possible that a diaphragmatic hernia is another rare manifestation of TSC and that TSC should be included in the differential diagnosis of infants with a diaphragmatic hernia. Given that both a horseshoe kidney and a diaphragmatic hernia are findings that can be detected prenatally on an ultrasound examination, our findings may have implications for prenatal genetic counseling.
View details for DOI 10.1002/ajmg.a.34197
View details for PubMedID 21910228
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Familial Cardiac Valvulopathy Due to Filamin A Mutation
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
2011; 155A (9): 2236-2241
Abstract
We report on the clinical findings in siblings affected by the recently characterized X-linked form of hereditary cardiac valvular dystrophy or cardiac valve disease (OMIM 314400) due to mutations in the FLNA gene and review the literature on this condition. Although FLNA related cardiac valve disease is presumed to be a rare disorder, it is likely underdiagnosed. Several features of this condition may aid in its identification. FLNA related valvular disease can be recognized on the basis of its distinctive inheritance, early age of onset, and frequent multi-valve involvement.
View details for DOI 10.1002/ajmg.a.34132
View details for PubMedID 21815255
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Medical and graduate students' attitudes toward personal genomics
GENETICS IN MEDICINE
2011; 13 (5): 400-408
Abstract
Medical schools are being approached by direct-to-consumer genotyping companies about genotyping faculty or trainees as a method to "teach" them about the potential implications of genotyping. In thinking about the future incorporation of genotyping into a graduate level genetics course, the purpose of this study was 2-fold: first, to assess knowledge, attitudes, and beliefs of students toward personal genomics as it related to themselves as both as customers and future physicians and as it related to consumers at large, and second, to determine the impact of the course (as taught without genotyping) on knowledge, attitudes, and beliefs.We surveyed first-year medical students and graduate students before and after a core genetics course.After the course, students were less likely to believe that genotyping information would be useful to physicians, patients, or consumers; genotyping would provide information to improve their own personal health; or personal genomic testing services are diagnostic of medical conditions. They were more likely to answer knowledge questions accurately after the course but still had difficulty with clinical interpretation. Despite these changes, a slight majority of students were, and remained, interested in undergoing genotyping themselves. Of note, the number who believed genotyping "would help them understand genetic concepts better than someone else's data" decreased. General curiosity was the most commonly chosen reason for interest in undergoing genotyping, and approximately 50% of respondents expressed concern about confidentiality of results.In conclusion, even without the genotyping process, an educational program about genotyping increased knowledge, particularly about the clinical limitations of genotyping, but student interest in genotyping did not significantly change. Institutions thinking about offering genotyping to their students as part of a learning experience should consider the pros and cons of doing so.
View details for DOI 10.1097/GIM.0b013e31820562f6
View details for Web of Science ID 000290435700005
View details for PubMedID 21270640
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Nuchal translucency measurement in fetuses with spinal muscular atrophy
PRENATAL DIAGNOSIS
2011; 31 (4): 327-330
Abstract
Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder with a high carrier frequency in the general population. The severity of this disorder indicates the importance of early prenatal detection. In medical literature, there are a few published case reports of enlarged nuchal translucency (NT) measurement in association with a diagnosis of SMA in the fetus. Our goal is to determine whether SMA in infants is associated with a history of an increased NT measurement during pregnancy.Using contact information obtained through SMA family support groups, women who had recently given birth to infants affected with SMA were identified and queried about NT ultrasound results during the pregnancy. NT values were confirmed via ultrasound report to determine whether SMA was associated with a history of an enlarged NT measurement.Twelve SMA affected infants with confirmed NT results during the pregnancy were identified. All fetuses had normal NT values ranging from 0.7 to 2.4 mm.In this series, SMA did not appear to be associated with an enlarged NT.
View details for DOI 10.1002/pd.2646
View details for Web of Science ID 000288620000002
View details for PubMedID 21287566
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Carpenter Syndrome: Extended RAB23 Mutation Spectrum and Analysis of Nonsense-mediated mRNA Decay
HUMAN MUTATION
2011; 32 (4): E2069-E2078
Abstract
Carpenter syndrome, a rare autosomal recessive disorder characterized by a combination of craniosynostosis, polysyndactyly, obesity, and other congenital malformations, is caused by mutations in RAB23, encoding a member of the Rab-family of small GTPases. In 15 out of 16 families previously reported, the disease was caused by homozygosity for truncating mutations, and currently only a single missense mutation has been identified in a compound heterozygote. Here, we describe a further 8 independent families comprising 10 affected individuals with Carpenter syndrome, who were positive for mutations in RAB23. We report the first homozygous missense mutation and in-frame deletion, highlighting key residues for RAB23 function, as well as the first splice-site mutation. Multi-suture craniosynostosis and polysyndactyly have been present in all patients described to date, and abnormal external genitalia have been universal in boys. High birth weight was not evident in the current group of patients, but further evidence for laterality defects is reported. No genotype-phenotype correlations are apparent. We provide experimental evidence that transcripts encoding truncating mutations are subject to nonsense-mediated decay, and that this plays an important role in the pathogenesis of many RAB23 mutations. These observations refine the phenotypic spectrum of Carpenter syndrome and offer new insights into molecular pathogenesis.
View details for DOI 10.1002/humu.21457
View details for Web of Science ID 000288464100002
View details for PubMedID 21412941
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NEWBORN WITH CHOROIDAL FISSURE CYST AND PANHYPOPITUITARISM
Western Regional Meeting of the American-Federation-for-Medical-Research
LIPPINCOTT WILLIAMS & WILKINS. 2011: 166–66
View details for Web of Science ID 000285542500296
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Prenatal genetic screening and diagnosis for pediatricians
CURRENT OPINION IN PEDIATRICS
2010; 22 (6): 809-813
Abstract
Prenatal genetic screening and diagnostic testing can identify many disorders that will require specialized newborn care and follow-up. Pediatricians should be aware of recent advances in testing that may have implications for their patients and families.Over the last half decade, there have been important changes in the breadth and depth of prenatal screening and diagnostic procedures. Carrier screening for selected genetic disorders is now offered routinely to pregnant women or those contemplating pregnancy. Newly developed strategies for first-trimester screening for fetal chromosome abnormalities have improved the detection rate for these disorders, while maintaining a low screen-positive rate. The American College of Obstetricians and Gynecologists and the American College of Medical Genetics now recommend that invasive prenatal diagnostic testing be made available to all pregnant women, regardless of age or prenatal screening results. And prenatal ultrasound findings of unknown clinical significance require that pediatricians provide appropriate follow-up in the newborn period and beyond.Prenatal genetic screening and diagnostic tests are changing rapidly, and results of these tests may impact the postnatal evaluation and treatment strategies for pediatric care.
View details for DOI 10.1097/MOP.0b013e32833f5f6e
View details for Web of Science ID 000284143600021
View details for PubMedID 20829690
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A Common Molecular Mechanism Underlies Two Phenotypically Distinct 17p13 1 Microdeletion Syndromes
AMERICAN JOURNAL OF HUMAN GENETICS
2010; 87 (5): 631-642
Abstract
DNA copy-number variations (CNVs) underlie many neuropsychiatric conditions, but they have been less studied in cancer. We report the association of a 17p13.1 CNV, childhood-onset developmental delay (DD), and cancer. Through a screen of over 4000 patients with diverse diagnoses, we identified eight probands harboring microdeletions at TP53 (17p13.1). We used a purpose-built high-resolution array with 93.75% breakpoint accuracy to fine map these microdeletions. Four patients were found to have a common phenotype including DD, hypotonia, and hand and foot abnormalities, constituting a unique syndrome. Notably, these patients were not affected with cancer. Moreover, none of the TP53-deletion patients affected with cancer (n = 4) had neurocognitive impairments. DD patients have larger deletions, which encompass but do not disrupt TP53, whereas cancer-affected patients harbor CNVs with at least one breakpoint within TP53. Most 17p13.1 deletions arise by Alu-mediated nonallelic homologous recombination. Furthermore, we identify a critical genomic region associated with DD and containing six underexpressed genes. We conclude that, although they overlap, 17p13.1 CNVs are associated with distinct phenotypes depending on the position of the breakpoint with respect to TP53. Further, detailed characterization of breakpoints revealed a common formation signature. Future studies should consider whether other loci in the genome also give rise to phenotypically distinct disorders by means of a common mechanism, resulting in a similar formation signature.
View details for DOI 10.1016/j.ajhg.2010.10.007
View details for Web of Science ID 000284668400008
View details for PubMedID 21056402
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Array-based technology and recommendations for utilization in medical genetics practice for detection of chromosomal abnormalities
GENETICS IN MEDICINE
2010; 12 (11): 742-745
Abstract
Laboratory evaluation of patients with developmental delay/intellectual disability, congenital anomalies, and dysmorphic features has changed significantly in the last several years with the introduction of microarray technologies. Using these techniques, a patient's genome can be examined for gains or losses of genetic material too small to be detected by standard G-banded chromosome studies. This increased resolution of microarray technology over conventional cytogenetic analysis allows for identification of chromosomal imbalances with greater precision, accuracy, and technical sensitivity. A variety of array-based platforms are now available for use in clinical practice, and utilization strategies are evolving. Thus, a review of the utility and limitations of these techniques and recommendations regarding present and future application in the clinical setting are presented in this study.
View details for DOI 10.1097/GIM.0b013e3181f8baad
View details for Web of Science ID 000284105800012
View details for PubMedID 20962661
View details for PubMedCentralID PMC3111046
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Clues to an Early Diagnosis of Kallmann Syndrome
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
2010; 152A (11): 2796-2801
Abstract
Kallmann syndrome (KS) is defined by the association of idiopathic hypogonadotropic hypogonadism and anosmia/hyposmia. Diagnosis is frequently delayed, however, because hypogonadotropic hypogonadism is usually not apparent until puberty and individuals with anosmia/hyposmia are often unaware of this sensory deficit. Mutations in at least six genes have been associated with KS; however, the sensitivity of molecular testing is only about 30% and, therefore, the diagnosis is largely based on clinical findings. We describe the findings in six individuals with KS, which demonstrate the utility of associated anomalies in making this diagnosis. Analysis of our case series and literature review suggests the consideration of KS for males with microphallus and/or cryptorchidism and for any patient with hearing loss, renal agenesis, and/or synkinesis. Conversely, patients with features of KS should have an audiology evaluation and a renal ultrasound.
View details for DOI 10.1002/ajmg.a.33442
View details for PubMedID 20949504
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Fibroblast Growth Factor Receptor 2 and Its Role in Caudal Appendage and Craniosynostosis
JOURNAL OF CRANIOFACIAL SURGERY
2010; 21 (5): 1346-1349
Abstract
Caudal appendage is a rare but reported finding seen in association with craniosynostosis. We report a newborn with caudal appendage secondary to sacrococcygeal eversion, a cloverleaf skull, choanal atresia, and a heterozygous mutation of Y375C in the juxtamembrane domain (exon 11) of fibroblast growth factor receptor 2 (FGFR2). Further support of this association are 22 other cases of craniosynostosis with caudal appendage or sacrococcygeal eversion in the literature. Of these, 19 had detectable mutations in FGFR2; 5, the same mutation; and 5, a similar substitution of cysteine for serine. We hypothesize that the association of craniosynostosis and caudal appendage is due to abnormal expression of FGFR2 in the tail bud of a developing embryo based on animal models. Our case and those reported in the literature suggest that in patients with caudal appendage and craniosynostosis, FGRF2 analysis should include regions outside the commonly tested exons 8 and 10, particularly the juxtamembrane domain.
View details for DOI 10.1097/SCS.0b013e3181ef2bab
View details for Web of Science ID 000282003300009
View details for PubMedID 20856019
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Analysis of the Size Distributions of Fetal and Maternal Cell-Free DNA by Paired-End Sequencing
CLINICAL CHEMISTRY
2010; 56 (8): 1279-1286
Abstract
Noninvasive prenatal diagnosis with cell-free DNA in maternal plasma is challenging because only a small portion of the DNA sample is derived from the fetus. A few previous studies provided size-range estimates of maternal and fetal DNA, but direct measurement of the size distributions is difficult because of the small quantity of cell-free DNA.We used high-throughput paired-end sequencing to directly measure the size distributions of maternal and fetal DNA in cell-free maternal plasma collected from 3 typical diploid and 4 aneuploid male pregnancies. As a control, restriction fragments of lambda DNA were also sequenced.Cell-free DNA had a dominant peak at approximately 162 bp and a minor peak at approximately 340 bp. Chromosome Y sequences were rarely longer than 250 bp but were present in sizes of <150 bp at a larger proportion compared with the rest of the sequences. Selective analysis of the shortest fragments generally increased the fetal DNA fraction but did not necessarily increase the sensitivity of aneuploidy detection, owing to the reduction in the number of DNA molecules being counted. Restriction fragments of lambda DNA with sizes between 60 bp and 120 bp were preferentially sequenced, indicating that the shotgun sequencing work flow introduced a bias toward shorter fragments.Our results confirm that fetal DNA is shorter than maternal DNA. The enrichment of fetal DNA by size selection, however, may not provide a dramatic increase in sensitivity for assays that rely on length measurement in situ because of a trade-off between the fetal DNA fraction and the number of molecules being counted.
View details for DOI 10.1373/clinchem.2010.144188
View details for Web of Science ID 000280501400016
View details for PubMedID 20558635
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Challenges in the clinical application of whole-genome sequencing
LANCET
2010; 375 (9727): 1749-1751
View details for DOI 10.1016/S0140-6736(10)60599-5
View details for Web of Science ID 000277890200036
View details for PubMedID 20434765
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Clinical assessment incorporating a personal genome
LANCET
2010; 375 (9725): 1525-1535
Abstract
The cost of genomic information has fallen steeply, but the clinical translation of genetic risk estimates remains unclear. We aimed to undertake an integrated analysis of a complete human genome in a clinical context.We assessed a patient with a family history of vascular disease and early sudden death. Clinical assessment included analysis of this patient's full genome sequence, risk prediction for coronary artery disease, screening for causes of sudden cardiac death, and genetic counselling. Genetic analysis included the development of novel methods for the integration of whole genome and clinical risk. Disease and risk analysis focused on prediction of genetic risk of variants associated with mendelian disease, recognised drug responses, and pathogenicity for novel variants. We queried disease-specific mutation databases and pharmacogenomics databases to identify genes and mutations with known associations with disease and drug response. We estimated post-test probabilities of disease by applying likelihood ratios derived from integration of multiple common variants to age-appropriate and sex-appropriate pre-test probabilities. We also accounted for gene-environment interactions and conditionally dependent risks.Analysis of 2.6 million single nucleotide polymorphisms and 752 copy number variations showed increased genetic risk for myocardial infarction, type 2 diabetes, and some cancers. We discovered rare variants in three genes that are clinically associated with sudden cardiac death-TMEM43, DSP, and MYBPC3. A variant in LPA was consistent with a family history of coronary artery disease. The patient had a heterozygous null mutation in CYP2C19 suggesting probable clopidogrel resistance, several variants associated with a positive response to lipid-lowering therapy, and variants in CYP4F2 and VKORC1 that suggest he might have a low initial dosing requirement for warfarin. Many variants of uncertain importance were reported.Although challenges remain, our results suggest that whole-genome sequencing can yield useful and clinically relevant information for individual patients.National Institute of General Medical Sciences; National Heart, Lung And Blood Institute; National Human Genome Research Institute; Howard Hughes Medical Institute; National Library of Medicine, Lucile Packard Foundation for Children's Health; Hewlett Packard Foundation; Breetwor Family Foundation.
View details for Web of Science ID 000277655100025
View details for PubMedID 20435227
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Partial ATRX Gene Duplication Causes ATR-X Syndrome
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
2009; 149A (10): 2317-2320
View details for DOI 10.1002/ajmg.a.33006
View details for Web of Science ID 000270745000043
View details for PubMedID 19764021
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Brachydactyly A-1 mutations restricted to the central region of the N-terminal active fragment of Indian Hedgehog
EUROPEAN JOURNAL OF HUMAN GENETICS
2009; 17 (9): 1112-1120
Abstract
Mutations in the gene Indian Hedgehog (IHH) that cause Brachydactyly A-1 (BDA1) have been restricted to a specific region of the N-terminal active fragment of Indian Hedgehog involving codons 95, 100, 131, and 154. We describe two novel mutations in codons 128 and 130, not previously implicated in BDA1. Furthermore, we identified an independent mutation at codon 131 and we also describe a New Zealand family, which carries the 'Farabee' founder mutation and haplotype. All of the BDA1 mutations occur in a restricted area of the N-terminal active fragment of the IHH and are in contrast to those mutations causing an autosomal recessive acrocapitofemoral dysplasia, whose mutations are located at the distal N- and C-terminal regions of IHH-N and are physically separated from the BDA1-causing mutations. The identification of multiple independent mutations in codons 95, 100, and now in 131, implicate a discrete function for this region of the protein. Finally, we present a clinical review of all reported and confirmed cases of BDA1, highlighting features of the disorder, which add to the spectrum of the IHH mutations.
View details for DOI 10.1038/ejhg.2009.18
View details for Web of Science ID 000269449900004
View details for PubMedID 19277064
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FOXC1 is required for normal cerebellar development and is a major contributor to chromosome 6p25.3 Dandy-Walker malformation
NATURE GENETICS
2009; 41 (9): 1037-U116
Abstract
Dandy-Walker malformation (DWM), the most common human cerebellar malformation, has only one characterized associated locus. Here we characterize a second DWM-linked locus on 6p25.3, showing that deletions or duplications encompassing FOXC1 are associated with cerebellar and posterior fossa malformations including cerebellar vermis hypoplasia (CVH), mega-cisterna magna (MCM) and DWM. Foxc1-null mice have embryonic abnormalities of the rhombic lip due to loss of mesenchyme-secreted signaling molecules with subsequent loss of Atoh1 expression in vermis. Foxc1 homozygous hypomorphs have CVH with medial fusion and foliation defects. Human FOXC1 heterozygous mutations are known to affect eye development, causing a spectrum of glaucoma-associated anomalies (Axenfeld-Rieger syndrome, ARS; MIM no. 601631). We report the first brain imaging data from humans with FOXC1 mutations and show that these individuals also have CVH. We conclude that alteration of FOXC1 function alone causes CVH and contributes to MCM and DWM. Our results highlight a previously unrecognized role for mesenchyme-neuroepithelium interactions in the mid-hindbrain during early embryogenesis.
View details for DOI 10.1038/ng.422
View details for Web of Science ID 000269382100019
View details for PubMedID 19668217
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Preaxial Hallucal Polydactyly as a Marker for Diabetic Embryopathy
BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY
2009; 85 (1): 13-19
Abstract
Diabetes is the most common endocrinologic complication during pregnancy, and poor control can lead to a variety of congenital anomalies in the fetus. However, it is often difficult to differentiate between diabetes-related anomalies and an underlying genetic syndrome. In the 1990s it was proposed that preaxial hallucal polydactyly, particularly when proximally placed, was a distinguishing feature of diabetic embryopathy.We summarize the clinical findings in 18 patients (five previously reported in abstract form) with diabetic embryopathy and preaxial hallucal polydactyly to determine which features are most suggestive of diabetic embryopathy.All 18 patients had preaxial hallucal polydactyly (seven bilateral, 11 unilateral), of which 15 patients had proximal implantation of the extra hallux. Further skeletal findings included the following: segmentation anomalies of the spine, equinovarus deformity of the feet, tibial hemimelia, hip dysplasia, and femoral hypoplasia. Upper limb malformations were rare. Eleven of the 18 mothers had prepregnancy insulin-dependent diabetes, while one mother had prepregnancy type 2 diabetes that required insulin therapy in the 3(rd) trimester. Five mothers had gestational diabetes that required insulin and one mother had gestational diabetes that was controlled by diet. The majority of mothers had poorly controlled diabetes during the pregnancy.Proximally placed preaxial hallucal polydactyly, particularly when coupled with segmentation anomalies of the spine and tibial hemimelia, is highly suggestive of diabetic embryopathy. Varying degrees of diabetes in the mothers point to a possible genetic predisposition interacting with the teratogenic effects of poor glycemic control leading to specific limb anomalies.
View details for DOI 10.1002/bdra.20503
View details for Web of Science ID 000262904800003
View details for PubMedID 18798547
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Clinical Utility of Array Comparative Genomic Hybridization: Uncovering Tumor Susceptibility in Individuals with Developmental Delay
JOURNAL OF PEDIATRICS
2009; 154 (1): 143-146
Abstract
Microarray-based comparative genomic hybridization can determine genome-wide copy number alterations at the kilobase level. We highlight the clinical utility of microarray-based comparative genomic hybridization in determining tumor susceptibility in 3 patients with dysmorphic features and developmental delay, likely decreasing both morbidity and mortality in these patients.
View details for DOI 10.1016/j.jpeds.2008.07.045
View details for Web of Science ID 000262272500031
View details for PubMedID 19187739
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Noninvasive diagnosis of fetal aneuploidy by shotgun sequencing DNA from maternal blood
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2008; 105 (42): 16266-16271
Abstract
We directly sequenced cell-free DNA with high-throughput shotgun sequencing technology from plasma of pregnant women, obtaining, on average, 5 million sequence tags per patient sample. This enabled us to measure the over- and underrepresentation of chromosomes from an aneuploid fetus. The sequencing approach is polymorphism-independent and therefore universally applicable for the noninvasive detection of fetal aneuploidy. Using this method, we successfully identified all nine cases of trisomy 21 (Down syndrome), two cases of trisomy 18 (Edward syndrome), and one case of trisomy 13 (Patau syndrome) in a cohort of 18 normal and aneuploid pregnancies; trisomy was detected at gestational ages as early as the 14th week. Direct sequencing also allowed us to study the characteristics of cell-free plasma DNA, and we found evidence that this DNA is enriched for sequences from nucleosomes.
View details for DOI 10.1073/pnas.0808319105
View details for Web of Science ID 000260597400037
View details for PubMedID 18838674
View details for PubMedCentralID PMC2562413
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Tibial Hemimelia with preaxial hallucal polydactyly in infants of diabetic mothers
WILEY-BLACKWELL. 2008: 291–91
View details for Web of Science ID 000256655000013
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Further delineation of deletion 1p36 syndrome in 60 patients: A recognizable phenotype and common cause of developmental delay and mental retardation
PEDIATRICS
2008; 121 (2): 404-410
Abstract
Deletion 1p36 syndrome is a recently delineated disorder, considered to be the most common subtelomeric microdeletion syndrome (1 in 5000 newborns). 1p36.3 deletions account for 0.5% to 1.2% of idiopathic mental retardation; thus, knowledge about the condition is important for pediatricians caring for such patients. Despite 100 reported cases, little is known about its natural history. Our aim was to delineate the natural history of deletion 1p36 and develop complete and accurate information with which to answer families' questions in the clinical setting.We evaluated 60 patients with the 1p36 deletion syndrome (41 female, 19 male). All underwent physical and neurologic assessments, and most received a psychological evaluation. Standard cytogenetics, fluorescence in situ hybridization of the subtelomeric regions, or array comparative genomic hybridization were used for diagnosis.Fourteen cases were detected by standard cytogenetics, and 46 were detected by fluorescence in situ hybridization of the subtelomeric regions or array comparative genomic hybridization. Occipitofrontal circumference was at < or = 2nd centile in 95%, and height and weight ranged between the < 3rd and 90th centiles. All patients had straight eyebrows, deep-set eyes, midface hypoplasia, broad nasal root/bridge, long philtrum, and pointed chin. Other features included microbrachycephaly (65%), epicanthus (50%), large, late-closing anterior fontanel (77%), and posteriorly rotated, low-set, abnormal ears (40%). Brachy/camptodactyly and short feet were prominent. Seventy-one percent exhibited heart defects, including 23% with a "noncompaction cardiomyopathy." Fifty-two percent had eye/visual abnormalities, and 64% had visual inattentiveness. Twenty-eight percent had sensorineural deafness, 41% had skeletal anomalies, 25% had abnormal genitalia, and 22% had renal abnormalities. Eighty-eight percent had central nervous system anomalies, and 44% had seizures. All patients demonstrated developmental delay with poor/absent speech; 95% had hypotonia. Twenty-six percent were able to walk alone, and 47% had a behavior disorder. Constant developmental progress was observed in all cases over time. Noncompaction cardiomyopathy and most seizures were controlled by pharmacotherapy.These 60 patients with deletion 1p36 represent the largest clinical series to date and provide new information on several aspects of this disorder, which is characterized by neurodevelopmental disability and a recognizable pattern of malformation.
View details for DOI 10.1542/peds.2007-0929
View details for Web of Science ID 000252877600021
View details for PubMedID 18245432
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Use of array-based technology in the practice of medical genetics
GENETICS IN MEDICINE
2007; 9 (9): 650-653
Abstract
Mental retardation affects approximately 3% of the population, and the background birth defect rate is 3% to 4%. An underlying cause is identified less than 50% of the time. In the cases in which a cause is determined, a chromosomal anomaly is the cause in up to 40%. Laboratory evaluation routinely includes high-resolution karyotyping, subtelomeric fluorescence in situ hybridization analysis, and targeted fluorescence in situ hybridization analysis depending on the clinical features. There are technical limitations to these techniques, however. For example, anomalies less than 2 to 3 Mb in size are undetectable by karyotype, and subtelomeric fluorescence in situ hybridization analysis is a labor-intensive analysis with a relatively low yield. With completion of the Human Genome Project, diagnostic testing is moving toward the use of DNA-based techniques such as comparative genomic hybridization microarray analysis or array comparative genomic hybridization. Although this technology has been used in the evaluation of tumors and cancer patients in the past, it is now being applied in the assessment of patients demonstrating idiopathic mental retardation or developmental delay, dysmorphic features, congenital anomalies, and spontaneous abortions. As with other well-developed cytogenetic studies, there are technical limitations to array comparative genomic hybridization that must be acknowledged and addressed before its widespread use. A variety of array-based technologies are now available on a clinical basis. We discuss the utility and limitations of using this technology in the evaluation of individuals with mental retardation and malformations, citing the existing literature.
View details for DOI 10.1097/GIM.0b013e31814cec3a
View details for Web of Science ID 000249640800013
View details for PubMedID 17873654
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Clinical features and management issues in Mowat-Wilson syndrome.
American journal of medical genetics. Part A
2006; 140 (24): 2730-2741
Abstract
Mowat-Wilson syndrome (MWS) is a relatively newly described multiple congenital anomaly/mental retardation syndrome. Haploinsufficiency of a gene termed ZFHX1B (also known as SIP1) on chromosome 2 is responsible for this condition, and clinical genetic testing for MWS recently became available. The majority of reports in the literature originate from Northern Europe and Australia. Here we report our clinical experience with 12 patients diagnosed with MWS within a 2-year period of time in the United States, with particular emphasis on clinical characteristics and management strategies. Individuals with this condition have characteristic facial features, including microcephaly, hypertelorism, medially flared and broad eyebrows, prominent columella, pointed chin, and uplifted earlobes, which typically prompt the clinician to consider the diagnosis. Medical issues in our cohort of patients included seizures (75%) with no predeliction for any particular seizure type; agenesis of the corpus callosum (60% of our patients studied); congenital heart defects (75%), particularly involving the pulmonary arteries and/or valves; hypospadias (55% of males); severely impaired or absent speech (100% of individuals over 1 year of age) with relatively spared receptive language; and Hirschsprung disease (50%) or chronic constipation (25%). The incidence of MWS is unknown, but based on the number of patients identified in a short period of time within the US, it is likely greatly under recognized. MWS should be considered in any individual with severely impaired or absent speech, especially in the presence of seizures and anomalies involving the pulmonary arteries (particularly pulmonary artery sling) or pulmonary valves.
View details for PubMedID 17103451
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Clinical features and management issues in Mowat-Wilson syndrome
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
2006; 140A (24): 2730-2741
View details for DOI 10.1002/ajmg.a.31530
View details for Web of Science ID 000242466200005
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Genitopatellar syndrome: expanding the phenotype and excluding mutations in LMX1B and TBX4.
American journal of medical genetics. Part A
2006; 140 (14): 1567-1572
Abstract
Genitopatellar syndrome is a newly described disorder characterized by absent/hypoplastic patellae, lower extremity contractures, urogenital anomalies, dysmorphic features, skeletal anomalies, and agenesis of the corpus callosum. More recently, cardiac anomalies and ectodermal dysplasia have been suggested as additional features of this syndrome. We report on two additional patients with genitopatellar syndrome and expand the spectrum of anomalies to include radio-ulnar synostosis. Since there exists significant overlap in the skeletal phenotype between genitopatellar syndrome and both the nail-patella and short patella syndromes, mutation screening of their causative genes, LMX1B and TBX4, was performed. Although there still does not appear to be an identifiable molecular etiology in genitopatellar syndrome, mutations in these two candidate genes have been excluded in our patients. Since both LMX1B and TBX4 are involved in a common molecular pathway, it is likely that the causative gene of genitopatellar syndrome functions within the same developmental process.
View details for PubMedID 16761293
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Genitopatellar syndrome: Expanding the phenotype and excluding mutations in LMX1B and TBX4
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
2006; 140A (14): 1567-1572
Abstract
Genitopatellar syndrome is a newly described disorder characterized by absent/hypoplastic patellae, lower extremity contractures, urogenital anomalies, dysmorphic features, skeletal anomalies, and agenesis of the corpus callosum. More recently, cardiac anomalies and ectodermal dysplasia have been suggested as additional features of this syndrome. We report on two additional patients with genitopatellar syndrome and expand the spectrum of anomalies to include radio-ulnar synostosis. Since there exists significant overlap in the skeletal phenotype between genitopatellar syndrome and both the nail-patella and short patella syndromes, mutation screening of their causative genes, LMX1B and TBX4, was performed. Although there still does not appear to be an identifiable molecular etiology in genitopatellar syndrome, mutations in these two candidate genes have been excluded in our patients. Since both LMX1B and TBX4 are involved in a common molecular pathway, it is likely that the causative gene of genitopatellar syndrome functions within the same developmental process.
View details for DOI 10.1002/ajmg.a.31258
View details for Web of Science ID 000238799900011
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Triplication of 8p22-8p23 in a patient with features similar to Kabuki syndrome.
American journal of medical genetics. Part A
2006; 140 (2): 170-173
Abstract
Kabuki syndrome (KS) comprises multiple congenital anomalies and distinctive facial appearance. Although a number of chromosome abnormalities have been described in patients with KS-like phenotypes, no consensus has been reached regarding the genetic basis underlying the classic Kabuki phenotype. A recent study reported on 8p22-8p23.1 duplication in patients diagnosed with KS; however, a number of other studies have not found this duplication in patients with classic KS. We report on a girl with triplication of 8p22-8p23 who has mental retardation and some features suggestive of KS, including growth retardation, left-sided obstructive heart lesion, long-appearing palpebral fissures, hypertelorism, sparse lateral eyebrows, prominent ears, and persistent fetal fingertip pads. She does not have the typical facial gestalt of KS, nor does she have other more specific findings of KS. We propose that abnormal copy number of genes in the 8p22-8p23 region results in a syndrome of multiple congenital anomalies with many features that overlap with classic KS. However, data from this patient and others with similar duplications in the literature suggest that duplication or triplication of 8p22-8p23 represents a recognizable pattern of malformation distinct from classic KS. The exact genetic abnormality underlying KS currently remains unknown.
View details for PubMedID 16353235
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Triplication of 8p22-8p23 in a patient with features similar to Kabuki syndrome
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
2006; 140A (2): 170-173
Abstract
Kabuki syndrome (KS) comprises multiple congenital anomalies and distinctive facial appearance. Although a number of chromosome abnormalities have been described in patients with KS-like phenotypes, no consensus has been reached regarding the genetic basis underlying the classic Kabuki phenotype. A recent study reported on 8p22-8p23.1 duplication in patients diagnosed with KS; however, a number of other studies have not found this duplication in patients with classic KS. We report on a girl with triplication of 8p22-8p23 who has mental retardation and some features suggestive of KS, including growth retardation, left-sided obstructive heart lesion, long-appearing palpebral fissures, hypertelorism, sparse lateral eyebrows, prominent ears, and persistent fetal fingertip pads. She does not have the typical facial gestalt of KS, nor does she have other more specific findings of KS. We propose that abnormal copy number of genes in the 8p22-8p23 region results in a syndrome of multiple congenital anomalies with many features that overlap with classic KS. However, data from this patient and others with similar duplications in the literature suggest that duplication or triplication of 8p22-8p23 represents a recognizable pattern of malformation distinct from classic KS. The exact genetic abnormality underlying KS currently remains unknown.
View details for DOI 10.1002/ajmg.a.31036
View details for Web of Science ID 000234491600012
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The diagnostic utility of a genetics evaluation in children with pervasive developmental disorders
GENETICS IN MEDICINE
2006; 8 (1): 50-54
Abstract
A genetics evaluation of children with pervasive developmental disorders (PDDs) identifies a diagnosis in 6% to 15% of cases. However, previous studies have not measured the incidence of genetic disorders among children with autistic-like features who do not necessarily meet the Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition criteria for PDD.We identified 101 patients at our institution referred for PDD, autism, Asperger syndrome, or autistic features. Seventy-eight were males and 23 were females, giving a male-to-female ratio of 3.4:1. No diagnosis was identified on examination alone, although Rett syndrome was suspected in six females. Seventeen patients did not undergo any type of testing because of noncompliance.Of the remaining 84 patients analyzed, seven (8.3%) were found to have abnormalities on testing. Three chromosomal anomalies were found: one with 5p duplication, one with low-level mosaicism for trisomy 21, and one with an unbalanced 10;22 translocation. Three females were diagnosed with Rett syndrome after MECP2 analysis identified a disease-causing mutation. The remaining patient was found to have an elevated urine orotic acid, with a normal ammonia level, of unknown significance.On the basis of our series, the yield of a genetics evaluation in patients with features of PDD who do not necessarily meet the Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition criteria is 8.3%. Approximately half of these were the result of a chromosomal abnormality. Three cases of Rett syndrome were identified for which autistic behaviors are a well-described feature. These findings suggest that a high-resolution karyotype provides the greatest diagnostic yield for patients with autistic-like features. MECP2 analysis should be considered for females who present with autistic behaviors.
View details for DOI 10.1097/01.gim.0000195304.45116.96
View details for Web of Science ID 000234850900007
View details for PubMedID 16418599
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Terminal deletion of 6p results in a recognizable phenotype.
American journal of medical genetics. Part A
2005; 136 (2): 162-168
Abstract
With improved cytogenetic techniques, small deletions and duplications are being identified with increased frequency. We report four cases with terminal deletions involving the 6p24- and 6p25-pter chromosomal segment who exhibit a distinct, recognizable pattern of malformations including hypertelorism, downslanting palpebral fissures, flat nasal bridge, Dandy-Walker malformation/variant, congenital heart defects, anterior eye-chamber abnormalities, hearing loss, and developmental delay. We also compare the clinical aspects of these patients to those of previously reported cases in the literature with similar terminal deletions of chromosome 6p. Routine chromosome analysis can miss this deletion, therefore, high-resolution chromosome analysis is indicated for individuals who exhibit these distinct features. Furthermore, individuals with this deletion should have an ophthalmologic exam, cardiac evaluation, head imaging, renal ultrasound, and formal hearing evaluation.
View details for PubMedID 15940702
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Terminal deletion of 6p results in a recognizable phenotype
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
2005; 136A (2): 162-168
Abstract
With improved cytogenetic techniques, small deletions and duplications are being identified with increased frequency. We report four cases with terminal deletions involving the 6p24- and 6p25-pter chromosomal segment who exhibit a distinct, recognizable pattern of malformations including hypertelorism, downslanting palpebral fissures, flat nasal bridge, Dandy-Walker malformation/variant, congenital heart defects, anterior eye-chamber abnormalities, hearing loss, and developmental delay. We also compare the clinical aspects of these patients to those of previously reported cases in the literature with similar terminal deletions of chromosome 6p. Routine chromosome analysis can miss this deletion, therefore, high-resolution chromosome analysis is indicated for individuals who exhibit these distinct features. Furthermore, individuals with this deletion should have an ophthalmologic exam, cardiac evaluation, head imaging, renal ultrasound, and formal hearing evaluation.
View details for DOI 10.1002/ajmg.a.30784
View details for Web of Science ID 000230229100009
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Detection of sonographic markers of fetal aneuploidy depends on maternal and fetal characteristics
10th Congress of the World-Federation-for-Ultrasound-in-Medicine-and-Biology
AMER INST ULTRASOUND MEDICINE. 2005: 811–15
Abstract
The purpose of this study was to determine factors that influence the detection rate of sonographic markers of fetal aneuploidy (SMFA).We reviewed the sonographic images of 160 consecutive second-trimester trisomic fetuses for the presence of SMFA, either structural anomalies or sonographic soft markers.One hundred forty-nine (93.1%) records were complete and analyzed; 78 cases (52.3%) were identified with 1 or more SMFA. Sonographic markers of fetal aneuploidy were detected in 42.7%, 75.0%, and 90.9% of trisomies 21, 18, and 13, respectively (P<.005). The detection rate of SMFA had a positive linear correlation with gestational age (adjusted R(2)=0.64; P<.002). Sonographic markers of fetal aneuploidy were detected in 43.7% of fetuses of less than 18.0 weeks' gestation and 64.5% of fetuses of 18.0 weeks' gestation or greater (likelihood ratio=6.4; P<.01). Sonographic markers of fetal aneuploidy were detected in 23.5% of patients with suboptimal image quality versus 58.3% of the others (likelihood ratio=7.5; P<.05). The rate of structural malformation was similar between the male and female fetuses, whereas that of soft markers was 49.4% in male and 30.0% in female fetuses (odds ratio=2.3; range, 1.2-4.5; P<.02). Factor analysis showed that some soft markers and some structural anomalies tended to appear together.The type of fetal trisomy, gestational age, sex, and quality of images influence the detection rate of SMFA. The highest detection rate for SMFA in the second trimester is at or above 18 weeks' gestational age. Certain markers are detected in clusters. These findings may explain, in part, the variability in reported rates of detection of SMFA among trisomic fetuses. These findings need to be prospectively tested in the general population of pregnancies for applicability to sonographic risk calculations for fetal trisomies.
View details for Web of Science ID 000229461900009
View details for PubMedID 15914685
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Autosomal dominant microtia and ocular coloboma: new syndrome or an extension of the oculo-auriculo-vertebral spectrum?
American journal of medical genetics. Part A
2005; 134 (4): 359-362
Abstract
The oculo-auriculo-vertebral (OAV) spectrum is an etiologically heterogeneous condition classically consisting of microtia, hemifacial microsomia, epibulbar dermoids, and vertebral anomalies. Other eye findings described in OAV include upper eyelid colobomas, ptosis, and varying degrees of microphthalmia or even anophthalmia. Iris and/or retinal colobomas have rarely been reported. We describe two familial cases of apparent OAV with ocular colobomas. We postulate that iris and/or retinal colobomas associated with OAV may represent a subgroup within the OAV spectrum with autosomal dominant inheritance, as in the families described herein. Since microtia can result from aberrant migration of neural crest cells into the first and second branchial arches during early embryonic development, and concomitant deficient neural crest migration into the developing eye can lead to ocular coloboma and or iris heterochromia, it may be that the altered gene or genes in our familial cases are involved with regulation of neural crest development.
View details for PubMedID 15800906
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Autosomal dominant microtia and ocular coloboma: New syndrome or an extension of the oculo-auriculo-vertebral spectrum?
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
2005; 134A (4): 359-362
View details for DOI 10.1002/ajmg.a.30638
View details for Web of Science ID 000228758400003
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Karyotype/phenotype correlations in duplication 4q: Evidence for a critical region within 4q27-28 for preaxial defects
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
2005; 134A (3): 334-337
View details for DOI 10.1002/ajmg.a.30644
View details for Web of Science ID 000228083600020
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Clinical and mutational spectrum of Mowat-Wilson Syndrome
EUROPEAN JOURNAL OF MEDICAL GENETICS
2005; 48 (2): 97-111
Abstract
Mowat-Wilson Syndrome is a recently delineated mental retardation syndrome usually associated with multiple malformations and a recognizable facial phenotype caused by defects of the transcriptional repressor ZFHX1B. To address the question of clinical and mutational variability, we analysed a large number of patients with suspected Mowat-Wilson Syndrome (MWS). Without prior knowledge of their mutational status, 70 patients were classified into "typical MWS", "ambiguous" and "atypical" groups according to their facial phenotype. Using FISH, qPCR and sequencing, ZFHX1B deletions, splice site or truncating mutations were detected in all 28 patients classified as typical MWS. No ZFHX1B defect was apparent in the remaining 15 cases with ambiguous facial features or in the 27 atypical patients. Genotype-phenotype analysis confirmed that ZFHX1B deletions and stop mutations result in a recognizable facial dysmorphism with associated severe mental retardation and variable malformations such as Hirschsprung disease and congenital heart defects. Our findings indicate that structural eye anomalies such as microphthalmia should be considered as part of the MWS spectrum. We also show that agenesis of the corpus callosum and urogenital anomalies (especially hypospadias) are significant positive predictors of a ZFHX1B defect. Based on our observation of affected siblings and the number of MWS cases previously reported, we suggest a recurrence risk of around 1%. The lack of missense mutations in MWS and MWS-like patients suggests there may be other, as yet unrecognized phenotypes, associated with missense mutations of this transcription factor.
View details for DOI 10.1016/j.ejmg.2005.01.003
View details for Web of Science ID 000230162200003
View details for PubMedID 16053902
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Kabuki syndrome: a review
CLINICAL GENETICS
2005; 67 (3): 209-219
Abstract
Kabuki syndrome (KS) (Kabuki make-up syndrome, Niikawa-Kuroki syndrome) is a multiple malformation/mental retardation syndrome that was described initially in Japan but is now known to occur in many other ethnic groups. It is characterized by distinctive facial features (eversion of the lower lateral eyelid, arched eyebrows with the lateral one-third dispersed or sparse, depressed nasal tip, and prominent ears), skeletal anomalies, dermatoglyphic abnormalities, short stature, and mental retardation. A number of other manifestations involving other organ systems can aid in the diagnosis and management of KS. This review will focus on the diagnostic criteria, the common and rare features of KS by organ system, and the possible etiology of this interesting condition.
View details for DOI 10.1111/j.1399-0004.2004.00348.x
View details for PubMedID 15691356
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Lateral meningocele syndrome: Vertical transmission and expansion of the phenotype
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
2005; 133A (2): 115-121
Abstract
Lateral meningoceles were first described by Lehman et al. [(1977); J Pediatr 90: 49-54] in a patient with other skeletal findings and distinctive craniofacial features. Subsequently, six more patients with the so-called lateral meningocele syndrome (LMS) have been reported. We describe the findings in three new cases and expand the phenotype. The existence of an affected mother and daughter supports the hypothesis that LMS is a dominant disorder affecting primarily the connective tissue.
View details for DOI 10.1002/ajmg.a.30526
View details for Web of Science ID 000227194100001
View details for PubMedID 15666314
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Developmental outcome in Kabuki syndrome
23rd David W Smith Workshop on Malformations and Morphogenesis
WILEY-LISS. 2005: 263–64
Abstract
Over the last 20 years, a wide spectrum of congenital anomalies have been described in association with Kabuki syndrome (KS). However, very little information is available on developmental outcome. As more individuals with this syndrome are recognized and reported, it appears that as many as one-sixth may have normal intelligence. The purpose of this report is to describe the developmental outcome in 15 patients with KS, to determine whether a recognizable pattern of disabilities exist, and whether developmental outcome correlates with the presence of malformations. We ascertained 15 patients with KS from three dysmorphology and clinical genetics services in which developmental milestones and formal developmental testing were available. Based on these patients and a review of the literature, in the absence of major structural brain anomalies, the average intelligence quotient (IQ) in patients with this condition fall within the mild mental retardation range, however, specific developmental outcomes are widely variable, ranging from severe MR to normal intelligence. The presence or absence of hearing loss or major malformations, other than those involving the brain, was not predictive of developmental outcome.
View details for DOI 10.1002/ajmg.a.30338
View details for Web of Science ID 000226181500007
View details for PubMedID 15523636
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Neonatal phenotype in Kabuki syndrome
23rd David W Smith Workshop on Malformations and Morphogenesis
WILEY-LISS. 2005: 244–47
Abstract
The Kabuki syndrome is a well-established pattern of human malformation with readily recognizable features, however the diagnosis is rarely made in the newborn period. The purpose of this study was to determine if there exists a neonatal phenotype for this disorder. We ascertained 16 infants evaluated in the first 28 days of life by a dysmorphologist who subsequently received the diagnosis of Kabuki syndrome. The average age of initial evaluation was 8 days and the average age of diagnosis was 2 years 6 months. Based on these findings, it is suggested that the distinctive clinical phenotype seen in older patients is also evident in the newborn period.
View details for DOI 10.1002/ajmg.a.30336
View details for Web of Science ID 000226181500003
View details for PubMedID 15690369
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Hydrops fetalis due to hepatic hemangioendothelioma: Skin lesions as a diagnostic clue.
LIPPINCOTT WILLIAMS & WILKINS. 2005: S136–S136
View details for Web of Science ID 000226539700344
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Terminal 22q deletion syndrome: A newly recognized cause of speech and language disability in the autism spectrum
PEDIATRICS
2004; 114 (2): 451-457
Abstract
Cryptic subtelomeric chromosome rearrangements account for 6% to 10% of idiopathic mental retardation. As cytogenetic and molecular techniques have become more sophisticated, the number of genetic syndromes attributed to these microdeletions has increased. To date, 64 patients have been described in the literature with a more recently recognized microdeletion syndrome, del 22q13.3. The purpose of this study is to present 11 new cases of this recently described syndrome to delineate further the phenotype and to alert the clinician to another genetic condition that should be considered in the differential diagnosis of early hypotonia, delayed speech acquisition, and autistic behavior.Eleven patients were evaluated in 3 academic institutions. Clinical features and results of cytogenetic testing were recorded and tabulated. Reasons for referral for genetic evaluation included developmental delay, severe expressive speech and language delay, and dysmorphic features.Age of presentation ranged from 5 months to 46 years. There were 10 female patients and 1 male patient. All of the patients exhibited delayed motor development, some degree of hypotonia, and severe expressive speech and language delay. Dysmorphic facial features included epicanthal folds, large cupped ears, underdeveloped philtrum, loss of cupid's bow, and full supraorbital ridges. Six patients exhibited autistic-like behaviors. Microscopically visible chromosome deletions were observed in 6 patients. In the remainder, the deletion was detected with the use of fluorescence in situ hybridization.Hypotonia and developmental delay are nonspecific findings observed in many malformation and genetic syndromes. However, in association with severe speech and language delay and autistic-like behavior, this phenotype may be a significant indication to consider the 22q13 deletion syndrome as a potential cause.
View details for PubMedID 15286229
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Uncommon FBN1 mutation in Marfan syndrome family with severe ectopia lentis
53rd Annual Meeting of the American-Society-of-Human-Genetics
CELL PRESS. 2003: 293–93
View details for Web of Science ID 000185599700724
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Clinical and molecular features of congenital disorder of glycosylation in patients with type 1 sialotransferrin pattern and diverse ethnic origins
JOURNAL OF PEDIATRICS
2002; 141 (5): 695-700
Abstract
To increase awareness of congenital disorders of glycosylation (CDG), we report the features of patients with a variety of clinical presentations ranging from mild hypotonia and strabismus to severe neurologic impairment.Nine North American patients with CDG type I and different ethnic origins were studied.All patients had transferrin isoelectric focusing studies with a type 1 sialotransferrin pattern. Molecular analysis showed the previously described R141H, V231M, and T237M PMM2 mutations in four patients as well as 3 rare mutations (DeltaC389, L104V, and IVS1 -1 G-->A) in the PMM2 gene in two Asian patients.The clinical features of these patients with diverse ethnic backgrounds confirm the variable course of CDG type I. Screening for CDG should be considered in children with relatively mild neurologic impairment, especially if they have suggestive findings such as cerebellar hypoplasia and abnormal fat distribution.
View details for DOI 10.1067/mpd.2002.128658
View details for PubMedID 12410200
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Karyotype/phenotype correlations in duplication 4q: evidence for a critical region within 4q27-31 for preaxial defects.
52nd Annual Meeting of the American-Society-of-Human-Genetics
CELL PRESS. 2002: 265–65
View details for Web of Science ID 000178025800543
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Prenatal diagnosis in the adolescent patient.
Adolescent medicine (Philadelphia, Pa.)
2002; 13 (2): 293-?
Abstract
Despite a 21% reduction in the birth rate for adolescents aged 15-19 years between 1991 and 2000, there are still over 470,000 births to adolescents nationwide. The primary purpose of prenatal screening is to determine the risk of a disease or condition affecting either the patient or her fetus. A determination of risk is possible only after an accurate assessment of all information unique to each pregnancy. This assessment includes a medical, obstetrical, social, and family history. Ethnicity-based screening tests should be offered to patients at risk for specific disorders unique to their ancestry, whereas population-based screening tests, such as maternal serum screening and ultrasound screening, should be offered to all pregnant women. Invasive diagnostic testing should be reserved for patients whose pregnancy has been determined to be at risk for a particular disease or condition.
View details for PubMedID 11986037
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Genetic Counseling and Screening of Consanguineous Couples and Their Offspring: Recommendations of the National Society of Genetic Counselors.
Journal of genetic counseling
2002; 11 (2): 97-119
Abstract
The objective of this document is to provide recommendations for genetic counseling and screening for consanguineous couples (related as second cousins or closer) and their offspring with the goals of1. providing preconception reproductive options2. improving pregnancy outcome and identifying reproductive choices3. reducing morbidity and mortality in the 1st years of life, and4. respecting psychosocial and multicultural issues.The recommendations are the opinions of a multicenter working group (the Consanguinity Working Group (CWG)) with expertise in genetic counseling, medical genetics, biochemical genetics, genetic epidemiology, pediatrics, perinatology, and public health genetics, which was convened by the National Society of Genetic Counselors (NSGC). The consensus of the CWG and NSGC reviewers is that beyond a thorough medical family history with follow-up of significant findings, no additional preconception screening is recommended for consanguineous couples. Consanguineous couples should be offered similar genetic screening as suggested for any couple of their ethnic group. During pregnancy, consanguineous couples should be offered maternal-fetal serum marker screening and high-resolution fetal ultrasonography. Newborns should be screened for impaired hearing and detection of treatable inborn errors of metabolism. These recommendations should not be construed as dictating an exclusive course of management, nor does use of such recommendations guarantee a particular outcome. The professional judgment of a health care provider, familiar with the facts and circumstances of a specific case, will always supersede these recommendations.
View details for DOI 10.1023/A:1014593404915
View details for PubMedID 26141656
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Intracranial hemorrhage in infants and children with hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)
PEDIATRICS
2002; 109 (1)
Abstract
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular dysplasia. Most cases are caused by mutations in the endoglin gene on chromosome 9 (HHT type 1) or the activin receptor-like kinase 1 gene on chromosome 12 (HHT type 2), which leads to telangiectases and arteriovenous malformations (AVM) of the skin, mucosa, and viscera. Epistaxis is the most frequent presentation. Visceral involvement includes pulmonary, gastrointestinal, and cerebral AVMs, which have been reported predominantly in adults. The purpose of this article is to describe 9 children who presented with intracranial hemorrhage (ICH) secondary to cerebral AVM. None of these children was suspected of having HHT before the incident, despite family histories of the disease.We report the first case of an ICH secondary to a cerebral AVM in a neonate confirmed to have HHT type 1 by molecular analysis. We also describe a series of 8 additional cases of ICH secondary to cerebral AVM in children presumed to have HHT. Examination of multiple affected members from each of these families, using well-accepted published criteria, confirmed the diagnosis of HHT. In addition, genetic linkage studies and/or mutation analysis identified endoglin as the disease-causing gene in 6 of these families. Autopsy, imaging studies, and/or surgery confirmed the presence of cerebral AVMs and ICH in all 9 cases.Our report shows that infants and children with a family history of HHT are at risk for sudden and catastrophic ICH. A preemptive diagnosis may potentially identify and prevent more serious sequelae.
View details for PubMedID 11773580
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Congenital hypomyelination neuropathy in a newborn infant: Unusual cause of diaphragmatic and vocal cord paralyses
PEDIATRICS
2001; 108 (5)
Abstract
We report a case of congenital hypomyelination neuropathy presenting at birth. The infant had generalized hypotonia and weakness. There was decreased respiratory effort along with a right phrenic nerve and left vocal cord paralyses. Tongue fasciculations were present. Deep tendon reflexes were absent in the upper extremities and hypoactive (1+) in the lower extremities. Magnetic resonance imaging of the head revealed no intracranial abnormalities, including normal cerebral myelination. Nerve conduction study showed absence of motor and sensory action potentials in the hands when the nerves in the upper limbs were stimulated. A motor response could be elicited only in the proximal leg muscles. Needle electromyography study was normal in the proximal limb muscles, but showed active denervation in the distal muscles of the arm and leg. These findings were thought to be consistent with a length-dependent sensorimotor peripheral polyneuropathy of axonal type with greater denervation of the distal muscles. A biopsy of the quadriceps muscle showed mild variability in fiber diameter, but no group typing or group atrophy. The muscle fibers showed no intrinsic abnormalities. Biopsy of the sural nerve showed scattered axons with very thin myelin sheaths. There was also a nearly complete loss of large diameter myelinated fibers. No onion bulb formations were noted. These findings were thought to be consistent with congenital hypomyelination neuropathy with a component of axonopathy. DNA analysis for identification of previously characterized mutations in the genes MPZ, PMP22, and EGR2 was negative. Several attempts at extubation failed and the infant became increasingly ventilator-dependent with increasing episodes of desaturation and hypercapnea. He also developed increasing weakness and decreased movement of all extremities. He underwent surgery at 2 months of age for placement of a gastrostomy tube and a tracheostomy. He was discharged from the hospital on a ventilator at 6 months of age. The infant was 13 months old at the time of submission of this report. Although he appears cognitively normal, he remains profoundly hypotonic and is on a home ventilator. There was no evidence of progressive weakness. Congenital hypomyelination neuropathy is a rare form of neonatal neuropathy that should be considered in the differential diagnosis of a newborn with profound hypotonia and weakness. It appears to be a heterogeneous disorder with some of the cases being caused by specific genetic mutations.
View details for PubMedID 11694679
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Scanning for telomeric deletions and duplications and uniparental disomy using genetic markers in 120 children with malformations
HUMAN GENETICS
2001; 109 (3): 311-318
Abstract
We screened 120 children with sporadic multiple congenital anomalies and either growth or mental retardation for uniparental disomy (UPD) or subtelomeric deletions. The screening used short tandem repeat polymorphisms (STRP) from the subtelomeric regions of 41 chromosome arms. Uninformative marker results were reanalyzed by using the next available marker on that chromosome arm. In total, approximately 25,000 genotypes were generated and analyzed for this study. Subtelomeric deletions of 1 Mb in size were excluded for 27 of 40 chromosome arms. Among the 120 subjects none was found to have UPD, but five subjects (4%, 95% confidence interval 1-9%) were found to have a deletion or duplication of one or more chromosome arms. We conclude that UPD is not a frequent cause of undiagnosed multiple congenital anomaly syndrome. In addition, we determined that 9p and 7q harbor chromosome length variations in the normal population. We conclude that subtelomeric marker analysis is effective for the detection of subtelomeric duplications and deletions, although it is labor intensive. Given a detection rate that is similar to prior studies and the large workload imposed by STRPs, we conclude that STRPs are an effective, but impractical, approach to the determination of segmental aneusomy given current technology.
View details for Web of Science ID 000171655300010
View details for PubMedID 11702212
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The spectrum and evolution of phenotypic findings in PTEN mutation positive cases of Bannayan-Riley-Ruvalcaba syndrome
JOURNAL OF MEDICAL GENETICS
2001; 38 (1): 52-58
View details for Web of Science ID 000166215500011
View details for PubMedID 11332402
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Transmission of the dysgnathia complex from mother to daughter
AMERICAN JOURNAL OF MEDICAL GENETICS
2000; 95 (3): 269-274
Abstract
We report the first observation of parent-to-child transmission of dysgnathia, a rare disorder characterized by severe mandibular hypoplasia or agenesis, ear anomalies, microstomia, and microglossia. Patient 1 was noted prenatally by ultrasound to have severe micrognathia and, after birth, abnormal ears with canal stenosis and non-contiguous lobules located dorsally to the rest of the pinnae, normal zygomata, severe jaw immobility and microstomia with an opening of only 4 to 5 mm, hypoplastic tongue, and cleft palate. The 21-year-old mother of patient 1 was born with severe micrognathia requiring tracheostomy, microglossia, cleft palate with filiform alveolar bands, abnormal pinnae, and decreased conductive hearing. Dysgnathia is thought to result from a defect in the development of the first branchial arch. A similar phenotype has been seen in Otx2 haplo-insufficiency and endothelin-1 homozygous null mice, suggesting that these genes contribute to branchial arch development. Our report of a long-surviving mother and her daughter with non-syndromal dysgnathia may lead to identification of the molecular basis of these findings and provide insight into the genetics of first branchial arch formation. The survival of patient 1 and patient 2 beyond the neonatal period has implications for improvements in prenatal diagnosis and counseling and for neonatal treatment of this condition.
View details for Web of Science ID 000090115100014
View details for PubMedID 11102934
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Recommendations for genetic counseling and screening of consanguineous couples and their offspring.
CELL PRESS. 2000: 42–42
View details for Web of Science ID 000089400700159
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Natural history of branchio-oto-renal (BOR) syndrome.
CELL PRESS. 2000: 56–56
View details for Web of Science ID 000089400700237
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The pediatric intern retreat: 20-year evolution of a continuing investment
ACADEMIC MEDICINE
2000; 75 (8): 853-857
Abstract
For the past 22 years the interns in pediatrics at the University of Washington and Children's Hospital and Regional Medical Center have been relieved of all clinical duties in order to participate in a five-day retreat. The retreat provides an opportunity for the interns to learn more about their classmates, build stronger bonds, and provide mutual support. This retreat has been supported by the hospital, the department of pediatrics, faculty, fellows, and community physicians. The authors describe the history of the Intern Retreat, present its goals, daily activities, and faculty, and discuss how the retreat is funded and supported by the hospital and the medical community.
View details for Web of Science ID 000088739800020
View details for PubMedID 10965868
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Detection of chromosomal aberrations by a whole-genome microsatellite screen
AMERICAN JOURNAL OF HUMAN GENETICS
2000; 66 (2): 419-427
Abstract
Chromosomal aberrations are a common cause of multiple anomaly syndromes that include developmental and growth retardation. Current microscopic techniques are useful for the detection of such aberrations but have a limit of resolution that is above the threshold for phenotypic effect. We hypothesized that a genomewide microsatellite screen could detect chromosomal aberrations that were not detected by standard cytogenetic techniques in a portion of these individuals. To test this hypothesis, we performed a genomewide microsatellite screen of patients, by use of a currently available genetic-marker panel that was originally designed for meiotic mapping of Mendelian traits. We genotyped approximately 400 markers on 17 pairs of parents and their children who had normal karyotypes. By using this approach, we detected and confirmed two cases of segmental aneusomy among 11 children with multiple congenital anomalies. These data demonstrate that a genomewide microsatellite scan can be used to detect chromosomal aberrations that are not detected by microscopic techniques.
View details for Web of Science ID 000088373100008
View details for PubMedID 10677301
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Inconsistencies in genetic counseling and screening for consanguineous couples and their offspring: The need for practice guidelines
GENETICS IN MEDICINE
1999; 1 (6): 286-292
Abstract
To determine current practices of genetic counseling and screening for consanguineous couples, their pregnancies and children, and to compare these practices to recommendations in the literature.A questionnaire was mailed to 1,582 board certified genetic counselors and medical geneticists in the United States.The return rate was 20% (n = 309). There was wide variation in the risk figures quoted to consanguineous couples to have offspring with birth defects and mental retardation (1% to 75% for incest between first-degree relatives, and 0.25% to 20% for first cousin unions). Suggested screening practices differed for consanguineous unions before conception, during pregnancy, following birth, and for children placed for adoption. Most respondents recommended screening based on ethnicity, yet disagreed as to which genetic disorders to include.To standardize genetic services, guidelines for screening the offspring of consanguineous unions are needed. A consensus should be reached as to the empirical risks for genetic disorders, birth defects, and mental retardation that may impair the offspring of consanguineous unions, with definition as to what these disorders are, and if the data applies to global populations. Guidelines should consider costs, the sensitivity and specificity of DNA and biochemical testing, and current practices of prenatal and newborn screening. Consideration should be given to screening based on ethnicity, particularly in populations where consanguineous unions are common, while remaining sensitive to cultural belief systems. Recommendations for screening healthy children from consanguineous unions to be placed for adoption pose ethical challenges.
View details for Web of Science ID 000084590600008
View details for PubMedID 11258630
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Phenotypic spectrum and management issues in Kabuki syndrome
JOURNAL OF PEDIATRICS
1999; 134 (4): 480-485
Abstract
To report the phenotypic spectrum and management issues of children with Kabuki syndrome (Niikawa-Kuroki syndrome) from North America.A case series of children (n = 18) with clinical findings of Kabuki syndrome.Medical genetics clinics in Washington, Alaska, and Arizona.Most patients had postnatal growth retardation, and all had developmental delay and hypotonia. Feeding difficulties, with or without cleft palate, were common; 5 patients required gastrostomy tube placement. Developmental quotients/IQs in all but 2 were 60 or less. Seizures were seen in less than half of the patients, but ophthalmologic and otologic problems were common, particularly recurrent otitis media. Congenital heart defects were present in 7 (39%); 3 patients underwent repair of coarctation of the aorta. Other features included urinary tract anomalies, malabsorption, joint hypermobility and dislocation, congenital hypothyroidism, idiopathic thrombocytopenic purpura, and in one patient, autoimmune hemolytic anemia and hypogammaglobulinemia. All patients had negative family histories for Kabuki syndrome.Kabuki syndrome is a mental retardation-malformation syndrome affecting multiple organ systems, with a broad spectrum of neuromuscular dysfunction and mental ability. Given that 18 ethnically diverse patients were identified from 2 genetics programs, it appears that this syndrome is more common in North American non-Japanese patients than previously appreciated.
View details for Web of Science ID 000079648400016
View details for PubMedID 10190924
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Heterozygous mutations in the gene encoding noggin affect human joint morphogenesis
NATURE GENETICS
1999; 21 (3): 302-304
Abstract
The secreted polypeptide noggin (encoded by the Nog gene) binds and inactivates members of the transforming growth factor beta superfamily of signalling proteins (TGFbeta-FMs), such as BMP4 (ref. 1). By diffusing through extracellular matrices more efficiently than TGFbeta-FMs, noggin may have a principal role in creating morphogenic gradients. During mouse embryogenesis, Nog is expressed at multiple sites, including developing bones. Nog-/- mice die at birth from multiple defects that include bony fusion of the appendicular skeleton. We have identified five dominant human NOG mutations in unrelated families segregating proximal symphalangism (SYM1; OMIM 185800) and a de novo mutation in a patient with unaffected parents. We also found a dominant NOG mutation in a family segregating multiple synostoses syndrome (SYNS1; OMIM 186500); both SYM1 and SYNS1 have multiple joint fusion as their principal feature. All seven NOG mutations alter evolutionarily conserved amino acid residues. The findings reported here confirm that NOG is essential for joint formation and suggest that NOG requirements during skeletogenesis differ between species and between specific skeletal elements within species.
View details for Web of Science ID 000078977900025
View details for PubMedID 10080184
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Expansile bone lesions in a three-generation family
AMERICAN JOURNAL OF MEDICAL GENETICS
1999; 82 (1): 1-5
Abstract
We report on a three-generation family with "expansile" bone lesions of the distal radius and ulna, cortical thickening of the proximal long bones, and pathologic fractures. The differential diagnosis of expansile bone lesions includes isolated bone cysts and tumors, such as enchondromas and fibrous dysplasia; familial expansile osteolysis; and the genochondromatoses. Our patients have findings most similar to the genochondromatoses; however, the distribution of the lesions and the accompanying manifestations may be evidence for a unique genetic condition in this family.
View details for Web of Science ID 000078009200001
View details for PubMedID 9916834
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Phenotypic differences in African Americans with Prader-Willi Syndrome
GENETICS IN MEDICINE
1998; 1 (1): 49-51
Abstract
We report on 10 African Americans with Prader-Willi syndrome whose features differ from those of white patients with this condition. Growth is less affected, hand and foot lengths usually are normal, and the facies are atypical; this may lead to underdiagnosis in this population. We encourage clinicians to recognize these phenotypic differences so that diagnosis is not overlooked.
View details for Web of Science ID 000082704300010
View details for PubMedID 11261430
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Shprintzen-Goldberg syndrome: A clinical analysis
AMERICAN JOURNAL OF MEDICAL GENETICS
1998; 76 (3): 202-212
Abstract
Shprintzen-Goldberg syndrome is one of a group of disorders characterized by craniosynostosis and marfanoid habitus. Eleven cases were reported previously. We present 4 new patients and review one of the patients of the original report of Shprintzen and Goldberg [1982: J Craniofac Genet Dev Biol 2:65-74], 15 years later. The clinical and radiologic findings on our patients are compared with those of the previously reported patients and also with those of Furlong et al. [1987: Am J Med Genet 26:599-604] and Lacombe and Battin [1993: Clin Dysmorphol 2: 220-224], who share many of the characteristics of Shprintzen-Goldberg syndrome. Some of the clinical data are helpful in determining if the patients of Furlong et al. [1987: Am J Med Genet 26:599-604] and Lacombe and Battin [1993: Clin Dysmorphol 2: 220-224] have a separate syndrome or represent a variant of Shprintzen-Goldberg syndrome. However, radiologic investigations appear to be more specific, since an abnormality of the first and second cervical vertebrae, hydrocephalus, dilatation of the lateral ventricles, and a Chiari-I malformation of the brain were found only in the patients with Shprintzen-Goldberg syndrome. The apparently diagnostic findings of the 15 patients with this syndrome may be helpful in differentiating between Shprintzen-Goldberg syndrome and other syndromes with craniosynostosis and marfanoid habitus.
View details for Web of Science ID 000072292400002
View details for PubMedID 9508238
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Digital anomalies, microcephaly, and normal intelligence: New syndrome or Feingold syndrome?
AMERICAN JOURNAL OF MEDICAL GENETICS
1997; 69 (3): 240-244
Abstract
We present four patients-two boys and their mother and an unrelated girl-with microcephaly, normal intelligence, and digital abnormalities. The hand abnormalities are characterized by brachydactyly with radial clinodactyly of the fourth and fifth fingers, ulnar clinodactyly of the second fingers, and an increased space between the second and third fingers associated with an abnormal palmar crease that extends to the ulnar border. The foot abnormalities include short toes with syndactyly of the fourth and fifth toes. The mother has normal intelligence, and her sons and the unrelated girl have normal development. Although similar digital abnormalities, microcephaly, and normal intelligence were described by Feingold in patients with gastrointestinal atresia, we think that our patients' findings represent a different condition. The most likely mode of inheritance is autosomal dominant. The clinical recognition of this syndrome will allow for appropriate genetic counseling as well as provision of information on natural history, i.e., normal intelligence.
View details for Web of Science ID A1997WQ31400006
View details for PubMedID 9096751
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Characterization of the split hand split foot malformation locus SHFM1 at 7q21.3-q22.1 and analysis of a candidate gene for its expression during limb development
HUMAN MOLECULAR GENETICS
1996; 5 (5): 571-579
Abstract
Split hand/split foot malformation (SHFM) is a heterogeneous limb developmental disorder, characterized by missing digits and fusion of remaining digits. An autosomal dominant form of this disorder (SHFM1) has been mapped to 7q21.3-q22.1 on the basis of SHFM-associated chromosomal rearrangements. Utilizing a YAC contig across this region, we have defined a critical interval of 1.5 Mb by the analysis of six interstitial deletion patients and mapped the translocation breakpoints of seven ectrodactyly patients within the interval. To delineate the basic molecular defect underlying SHFM, we have searched for candidate genes in a 500 kb region containing five of the translocation breakpoints. Three genes were identified, two genes of the Distal-less (dii) homeobox gene family, DLX5 and DLX6 and a novel gene, which we named DSS1. DSS1 is predicted to encode a highly acidic polypeptide with no significant similarity to any known proteins but 100% amino acid sequence identify with its murine homolog (Dss1). Using RNA in situ hybridization analysis, we detected a tissue-specific expression profile for Dss1 in limb bud, craniofacial primordia and skin. A deficiency in expression of Dss1, DLX5 and/or DLX6 during development may explain the SHFM phenotypes.
View details for Web of Science ID A1996UJ74300002
View details for PubMedID 8733122
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ISOLATED PERSISTENT HYPERMETHIONINEMIA
AMERICAN JOURNAL OF HUMAN GENETICS
1995; 57 (4): 882-892
Abstract
New information has been obtained on 30 patients with isolated persistent hypermethioninemia, most of them previously unreported. Biopsies to confirm the presumptive diagnosis of partially deficient activity of ATP: L-methionine S-adenosyltransferase (MAT; E.C.2.5.1.6) in liver were not performed on most of these patients. However, none showed the clinical findings or the extreme elevations of serum folate previously described in other patients with isolated hypermethioninemia considered not to have hepatic MAT deficiency. Patients ascertained on biochemical grounds had no neurological abnormalities, and 27/30 had IQs or Bayley development-index scores within normal limits or were judged to have normal mental development. Methionine transamination metabolites accumulated abnormally only when plasma methionine concentrations exceeded 300-350 microM and did so more markedly after 0.9 years of age. Data were obtained on urinary organic acids as well as plasma creatinine concentrations. Patterns of inheritance of isolated hypermethioninemia were variable. Considerations as to the optimal management of this group of patients are discussed.
View details for Web of Science ID A1995RV79300020
View details for PubMedID 7573050
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A BALANCED Y-16 TRANSLOCATION ASSOCIATED WITH TURNER-LIKE NEONATAL LYMPHEDEMA SUGGESTS THE LOCATION OF A POTENTIAL ANTI-TURNER GENE ON THE Y-CHROMOSOME
3rd International Workshop on Human Chromosome 18 Mapping 1995
KARGER. 1995: 163–67
Abstract
A male patient with Turner-like hydrops in the newborn period (Bonnevie-Ullrich syndrome) was studied. The karyotype was 46,X,t(Y;16)(q11.2;q24) in 100 cells. Chromosome painting with the heterochromatic Y chromosome-specific long arm repeat DYZ2 disclosed that all the hybridization was on the derivative 16. This was confirmed by chromosome painting with DYZ1, the other major Y long arm heterochromatic repeat, and DYZ3, the Y alphoid, centromeric repeat which showed chromosomal separation of the 2 stained regions. To further localize the breakpoint, FISH was performed using individual YACs from a Y-YAC contig (Foote et al., 1992). This disclosed two YACs (yOX111 and yOX123) which hybridized to both the Y and der16 chromosomes. The YACS spanning the translocation breakpoint region were located just proximal to the Y heterochromatin boundary. The recent discovery of a candidate gene for the azoospermia factor (AZF) in this region (Ma et al., 1993) suggests the possibility that there are several Y-expressed genes adjacent to the heterochromatin boundary (as there are near the pseudoautosomal boundary) which may include a gene involved with lymphedema which is disrupted by the translocation in this patient.
View details for Web of Science ID A1995RV53400013
View details for PubMedID 7656589
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MOLECULAR MAPPING OF THE EDWARDS-SYNDROME PHENOTYPE TO 2 NONCONTIGUOUS REGIONS ON CHROMOSOME-18
AMERICAN JOURNAL OF HUMAN GENETICS
1994; 55 (3): 476-483
Abstract
In an effort to identify regions on chromosome 18 that may be critical in the appearance of the Edwards syndrome phenotype, we have analyzed six patients with partial duplication of chromosome 18. Four of the patients have duplications involving the distal half of 18q (18q21.1-qter) and are very mildly affected. The remaining two patients have most of 18q (18q12.1-qter) duplicated, are severely affected, and have been diagnosed with Edwards syndrome. We have employed FISH, using DNA probes from a chromosome 18-specific library, for the precise determination of the duplicated material in each of these patients. The clinical features and the extent of the chromosomal duplication in these patients were compared with four previously reported partial trisomy 18 patients, to identify regions of chromosome 18 that may be responsible for certain clinical features of trisomy 18. The comparative analysis confirmed that there is no single region on 18q that is sufficient to produce the trisomy 18 phenotype and identified two regions on 18q that may work in conjunction to produce the Edwards syndrome phenotype. In addition, correlative analysis indicates that duplication of 18q12.3-q22.1 may be associated with more severe mental retardation in trisomy 18 individuals.
View details for Web of Science ID A1994PF50900009
View details for PubMedID 8079991
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DOWN-SYNDROME PHENOTYPES - THE CONSEQUENCES OF CHROMOSOMAL IMBALANCE
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
1994; 91 (11): 4997-5001
Abstract
Down syndrome (DS) is a major cause of mental retardation and congenital heart disease. Besides a characteristic set of facial and physical features, DS is associated with congenital anomalies of the gastrointestinal tract, an increased risk of leukemia, immune system defects, and an Alzheimer-like dementia. Moreover, DS is a model for the study of human aneuploidy. Although usually caused by the presence of an extra chromosome 21, subsets of the phenotypic features of DS may be caused by the duplication of small regions of the chromosome. The physical map of chromosome 21 allows the molecular definition of the regions duplicated in these rare cases of partial trisomy. As a first step in identifying the genes responsible for individual DS features and their pathophysiology, a panel of cell lines derived from 16 such individuals has been established and the molecular break points have been determined using fluorescence in situ hybridization and Southern blot dosage analysis of 32 markers unique to human chromosome 21. Combining this information with detailed clinical evaluations of these patients, we have now constructed a "phenotypic map" that includes 25 features and assigns regions of 2-20 megabases as likely to contain the genes responsible. This study provides evidence for a significant contribution of genes outside the D21S55 region to the DS phenotypes, including the facies, microcephaly, short stature, hypotonia, abnormal dermatoglyphics, and mental retardation. This strongly suggests DS is a contiguous gene syndrome and augurs against a single DS chromosomal region responsible for most of the DS phenotypic features.
View details for Web of Science ID A1994NN21400082
View details for PubMedID 8197171
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JARCHO-LEVIN SYNDROME - UNUSUAL SURVIVAL IN A CLASSICAL CASE
AMERICAN JOURNAL OF MEDICAL GENETICS
1994; 49 (3): 328-332
Abstract
Spondylothoracic dysostosis, or Jarcho-Levin syndrome, together with spondylocostal dysostosis, constitute a heterogeneous group of rare disorders characterized by short-neck, short-trunk dwarfism and multiple vertebral anomalies at all levels of the vertebral column. The latter include hemivertebrae, fused, hypoplastic, and "butterfly" vertebrae. In most cases of Jarcho-Levin syndrome, the small size of the thorax causes respiratory death in infancy. This report of a Puerto Rican child with spondylothoracic dysostosis and unusually long survival to 11 years exemplifies the nosologic and prognostic difficulties associated with this syndrome.
View details for Web of Science ID A1994MT95300016
View details for PubMedID 8209895
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INTRAVENOUS IMMUNOGLOBULIN THERAPY FOR TOXIC SHOCK SYNDROME
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
1992; 267 (24): 3315-3316
Abstract
Staphylococcus aureus and group A Streptococcus pyogenes produce toxic shock syndrome characterized by hypotension and multisystem organ failure. While conventional therapy has consisted of antibiotics and intensive supportive care, some experimental evidence suggests that immunoglobulins directed against the toxins may be effective additional therapy. We report a case of "toxic strep syndrome" in which intravenous immunoglobulin was administered when signs and symptoms were worsening while the patient was receiving conventional therapy. Within hours of administration of the intravenous immunoglobulin, the patient experienced dramatic clinical improvement. This response suggests a possible therapeutic benefit of intravenous immunoglobulin in toxic shock syndrome.
View details for Web of Science ID A1992HY94400031
View details for PubMedID 1597914
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EARLY CIRRHOSIS IN SURVIVORS WITH JEUNE THORACIC DYSTROPHY
JOURNAL OF PEDIATRICS
1992; 120 (5): 754-756
Abstract
Two siblings with Jeune thoracic dystrophy had persistent evidence of hepatic dysfunction; one had cirrhosis. Liver disease, a significant problem in patients who survive this condition, may be progressive in some.
View details for Web of Science ID A1992HT98100016
View details for PubMedID 1578311
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HAND AND FOOT LENGTH IN PRADER-WILLI SYNDROME
AMERICAN JOURNAL OF MEDICAL GENETICS
1991; 41 (1): 5-9
Abstract
Small hands and feet (acromicria) are often cited as manifestations in the Prader-Willi syndrome (PWS), but it has been our experience that these are not universal findings. To address this issue, we obtained longitudinal and cross-sectional data, retrospectively and prospectively, including height, hand length, and foot length, on 56 patients with PWS who are followed in the multidisciplinary PWS clinic at the University of Connecticut Health Center. Hand and foot lengths were plotted using two published sets of normative data. In addition, height age was calculated on each measurement of stature so that the corresponding hand and foot measurements could be compared to those expected for height, rather than age, as many PWS individuals are short. Foot length was proportionately smaller than hand length in all individuals; this difference was more striking in females. By age 12 years, almost all individuals had a foot length less than 25th centile for chronological age and less than 50th centile for height age. Female hand length was also less than 25th centile for chronological by age 12 years and less than 50th centile for height age in almost all cases. Male hand length data appeared to fall more within the normal range until adulthood, although fewer data were available. Black individuals with PWS had relatively larger hands and feet than their Caucasian counterparts. Many people with PWS had hand and foot lengths which fell within the normal range, particularly those under the age of 12 years and those whose height was greater than 50th centile for age.(ABSTRACT TRUNCATED AT 250 WORDS)
View details for Web of Science ID A1991GH55200002
View details for PubMedID 1951464
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LINKAGE ANALYSIS IN MARFAN-SYNDROME
JOURNAL OF MEDICAL GENETICS
1990; 27 (2): 86-90
Abstract
We have analysed 40 marker loci on 13 chromosomes for linkage with Marfan syndrome. None of the loci was linked to the Marfan syndrome locus at theta = 0.00. This study provides a basis for an exclusion map and for further collaboration in mapping of the locus.
View details for Web of Science ID A1990CM25600004
View details for PubMedID 1969490