Christina (Christy) Tise, MD, PhD

All Publications

• Molecular Testing in Newborn Screening: VUS Burden Among True Positives and Secondary Reproductive Limitations via Expanded Carrier Screening Panels. Genetics in medicine : official journal of the American College of Medical Genetics Cook, S., Dunn, E., Kornish, J., Calderwood, L., Campion, M., Cusmano-Ozog, K. P., Tise, C. G. 2023: 101055

  Abstract

  PURPOSE: Expanded carrier screening (ECS) gene panels have several limitations including variable content, current knowledge of disease-causing variants, and differing reporting policies. This study evaluated if the disease-associated variants identified in affected neonates who screened positive by California newborn screening (NBS) for an inherited metabolic disorder (IMD) by tandem mass spectrometry (MS/MS) would likely be reported by ECS gene panels.METHODS: Retrospective review of neonates referred by the California Department of Public Health for a positive NBS by multianalyte MS/MS from 01/01/20 through 06/30/21.RESULTS: One hundred thirty-six neonates screened positive for ≥1 NBS MS/MS indication. Nineteen neonates (14%) were ultimately diagnosed with an IMD, all of whom had abnormal biochemical testing. Eighteen of the 19 underwent molecular testing; 10 (56%) neonates had ≥1 VUS, of whom nine were of non-White ancestry. ECS panels would have been negative for 56% (20/36) of parents with an affected neonate, 85% (17/20) of whom were of non-White ancestry.CONCLUSIONS: The number of VUS identified in this cohort highlights the need for more diversified variant databases. Due in part to the lack of diversity in currently sequenced populations, genomic sequencing cannot replace biochemical testing for the diagnosis of an IMD.

  View details for DOI 10.1016/j.gim.2023.101055

  View details for PubMedID 38146699

• MT-ATP6 mitochondrial disease identified by newborn screening reveals a distinct biochemical phenotype. American journal of medical genetics. Part A Tise, C. G., Verscaj, C. P., Mendelsohn, B. A., Woods, J., Lee, C. U., Enns, G. M., Stander, Z., Hall, P. L., Cowan, T. M., Cusmano-Ozog, K. P. 2023

  Abstract

  Although decreased citrulline is used as a newborn screening (NBS) marker to identify proximal urea cycle disorders (UCDs), it is also a feature of some mitochondrial diseases, including MT-ATP6 mitochondrial disease. Here we describe biochemical and clinical features of 11 children born to eight mothers from seven separate families who were identified with low citrulline by NBS (range 3-5muM; screening cutoff >5) and ultimately diagnosed with MT-ATP6 mitochondrial disease. Follow-up testing revealed a pattern of hypocitrullinemia together with elevated propionyl-(C3) and 3-hydroxyisovaleryl-(C5-OH) acylcarnitines, and a homoplasmic pathogenic variant in MT-ATP6 in all cases. Single and multivariate analysis of NBS data from the 11 cases using Collaborative Laboratory Integrated Reports (CLIR; https://clir.mayo.edu) demonstrated citrulline <1st percentile, C3>50th percentile, and C5-OH >90th percentile when compared with reference data, as well as unequivocal separation from proximal UCD cases and false-positive low citrulline cases using dual scatter plots. Five of the eight mothers were symptomatic at the time of their child(ren)'s diagnosis, and all mothers and maternal grandmothers evaluated molecularly and biochemically had a homoplasmic pathogenic variant in MT-ATP6, low citrulline, elevated C3, and/or elevated C5-OH. All molecularly confirmed individuals (n=17) with either no symptoms (n=12), migraines (n=1), or a neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP) phenotype (n=3) were found to have an A or U mitochondrial haplogroup, while one child with infantile-lethal Leigh syndrome had a B haplogroup.

  View details for DOI 10.1002/ajmg.a.63159

  View details for PubMedID 36883293

• Neonatal lupus is a novel cause of positive newborn screening for X-linked adrenoleukodystrophy. American journal of medical genetics. Part A Niehaus, A. D., Mendelsohn, B. A., Zimmerman, B., Lee, C. U., Manning, M. A., Cusmano-Ozog, K. P., Tise, C. G. 2023

  Abstract

  We report three unrelated individuals, each exposed to maternal autoantibodies during gestation and found to have elevated very long-chain fatty acids (VLCFAs) in the newborn period after screening positive by California newborn screening (NBS) for X-linked adrenoleukodystrophy (ALD). Two probands presented with clinical and laboratory features of neonatal lupus erythematosus (NLE); the third had features suggestive of NLE and a known maternal history of Sjogren's syndrome and rheumatoid arthritis. In all three individuals, subsequent biochemical and molecular evaluation for primary and secondary peroxisomal disorders was nondiagnostic with normalization of VLCFAs by 15months of age. These cases add to the expanding differential diagnosis to consider in newborns who screen positive for ALD via elevated C26:0-lysophosphatidylcholine. Though the pathophysiology of how transplacental maternal anti-Ro antibodies damage fetal tissue is not well-understood, we postulate that the VLCFA elevations reflect a systemic inflammatory response and secondary peroxisomal dysfunction that improves once maternal autoantibodies wane after birth. Additional evaluation of this phenomenon is warranted to better understand the intricate biochemical, clinical, and possible therapeutic overlap between autoimmunity, inflammation, peroxisomal dysfunction, and human disease.

  View details for DOI 10.1002/ajmg.a.63144

  View details for PubMedID 36863699

• Medical genetics training in the COVID-19 era: A resident's perspective. American journal of medical genetics. Part A Tise, C. G. 2021

  View details for DOI 10.1002/ajmg.a.62379

  View details for PubMedID 34096675

• Unexpected diagnoses in patients with abnormal newborn screening Tise, C., Velez-Bartolomei, F., Morales, J., Lee, C., Bernstein, J., Enns, G. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2021: S354

  View details for Web of Science ID 000639219800534

• Aicardi-Goutières syndrome may present with positive newborn screen for X-linked adrenoleukodystrophy. American journal of medical genetics. Part A Tise, C. G., Morales, J. A., Lee, A. S., Velez-Bartolomei, F. n., Floyd, B. J., Levy, R. J., Cusmano-Ozog, K. P., Feigenbaum, A. S., Ruzhnikov, M. R., Lee, C. U., Enns, G. M. 2021

  Abstract

  We report three unrelated probands, two male and one female, diagnosed with Aicardi-Goutières syndrome (AGS) after screening positive on California newborn screening (CA NBS) for X-linked adrenoleukodystrophy (X-ALD) due to elevated C26:0 lysophosphatidylcholine (C26:0-LPC). Follow-up evaluation was notable for elevated C26:0, C26:1, and C26:0/C22:0 ratio, and normal red blood cell plasmalogens levels in all three probands. Diagnoses were confirmed by molecular sequencing prior to 12 months of age after clinical evaluation was inconsistent with X-ALD or suggestive of AGS. For at least one proband, the early diagnosis of AGS enabled candidacy for enrollment into a therapeutic clinical trial. This report demonstrates the importance of including AGS on the differential diagnosis for individuals who screen positive for X-ALD, particularly infants with abnormal neurological features, as this age of onset would be highly unusual for X-ALD. While AGS is not included on the Recommended Universal Screening Panel, affected individuals can be identified early through state NBS programs so long as providers are aware of a broader differential that includes AGS. This report is timely, as state NBS algorithms for X-ALD are actively being established, implemented, and refined.

  View details for DOI 10.1002/ajmg.a.62160

  View details for PubMedID 33683010

• Genetics of recurrent pregnancy loss: a review. Current opinion in obstetrics & gynecology Tise, C. G., Byers, H. M. 2021

  Abstract

  Human reproduction is remarkably inefficient; with pregnancy loss occurring in 10-30% of clinically recognized pregnancies. Of those, 3-5% of couples experience recurrent pregnancy loss (RPL), more than 50% of who never receive an underlying diagnosis. Herein, we review evidence that genetic changes, including pathogenic variant(s) in highly penetrant genes, may provide an explanation for a proportion of couples with pregnancy loss.Genetic abnormalities that may predispose to pregnancy loss include chromosomal aneuploidy, copy number variants, single-gene changes and others. Although previously limited by the need for hypothesis-driven assessment, advancement of various molecular technologies have sheparded in the opportunity to identify molecular cause of highly heterogeneous conditions, including RPL. The identification of causative genetic aberrations associated with RPL demonstrates a promising area of further research.The journey of human development from a single-cell zygote to a term infant is complex process. Early research into copy number variants and highly penetrant single-gene changes may provide diagnosis for a proportion of couples with RPL as well as inform genes critical for early human development.

  View details for DOI 10.1097/GCO.0000000000000695

  View details for PubMedID 33605623

• From Genotype to Phenotype: Nonsense Variants in SLC13A1 Are Associated with Decreased Serum Sulfate and Increased Serum Aminotransferases G3-GENES GENOMES GENETICS Tise, C. G., Perry, J. A., Anforth, L. E., Pavlovich, M. A., Backman, J. D., Ryan, K. A., Lewis, J. P., O'Connell, J. R., Yerges-Armstrong, L. M., Shuldiner, A. R. 2016; 6 (9): 2909-2918

  Abstract

  Using genomic applications to glean insights into human biology, we systematically searched for nonsense single nucleotide variants (SNVs) that are rare in the general population but enriched in the Old Order Amish (Amish) due to founder effect. We identified two nonlinked, nonsense SNVs (R12X and W48X) in SLC13A1 (allele frequencies 0.29% and 0.74% in the Amish; enriched 1.2-fold and 3.7-fold, compared to the outbred Caucasian population, respectively). SLC13A1 encodes the apical sodium-sulfate cotransporter (NaS1) responsible for sulfate (re)absorption in the kidneys and intestine. SLC13A1 R12X and W48X were independently associated with a 27.6% (P = 2.7 × 10(-8)) and 27.3% (P = 6.9 × 10(-14)) decrease in serum sulfate, respectively (P = 8.8 × 10(-20) for carriers of either SLC13A1 nonsense SNV). We further performed the first exome- and genome-wide association study (ExWAS/GWAS) of serum sulfate and identified a missense variant (L348P) in SLC26A1, which encodes the basolateral sulfate-anion transporter (Sat1), that was associated with decreased serum sulfate (P = 4.4 × 10(-12)). Consistent with sulfate's role in xenobiotic detoxification and protection against acetaminophen-induced hepatotoxicity, SLC13A1 nonsense SNV carriers had higher aminotransferase levels compared to noncarriers. Furthermore, SLC26A1 L348P was associated with lower whole-body bone mineral density (BMD) and higher serum calcium, consistent with the osteochondrodysplasia exhibited by dogs and sheep with naturally occurring, homozygous, loss-of-function mutations in Slc13a1 This study demonstrates the power and translational potential of systematic identification and characterization of rare, loss-of-function variants and warrants additional studies to better understand the importance of sulfate in human physiology, disease, and drug toxicity.

  View details for DOI 10.1534/g3.116.032979

  View details for Web of Science ID 000384021400022

  View details for PubMedID 27412988

  View details for PubMedCentralID PMC5015947

• Fetal phenotype and diagnosis of autosomal dominant Robinow syndrome due to novel DVL1 variant. Prenatal diagnosis Smith, C. M., Guinon, K., Bachir, S., Tise, C. G. 2024

  Abstract

  Due to abnormal prenatal ultrasound findings of femoral shortening and flattened facial profile, a G2P0 pregnant patient underwent an amniocentesis at 15 weeks of gestation for proband-only exome sequencing. Bioinformatic filtering for genes included on the laboratory's extended skeletal dysplasia panel identified a heterozygous, likely pathogenic, frameshift variant in DVL1 NM_001330311.2:c.1575_1582dup; (p.Pro528ArgfsTer149). Pathogenic variants in DVL1 are associated with autosomal dominant Robinow syndrome (ADRS), a genetic disorder characterized by skeletal dysplasia with genital and craniofacial abnormalities. Prenatal ultrasound in the third trimester noted shortened long bones (first percentile for gestational age), macrocephaly with frontal bossing, short and upturned nose with a wide nasal root, triangular mouth, low pedal arches concerning for rocker-bottom feet, and ambiguous genitalia. A postnatal exam by Medical Genetics confirmed the prenatal findings in addition to hypertelorism, brachydactyly with broad thumbs and halluces, clinodactyly of second fingers, rigid gums with a frontal frenulum, and a sacral dimple. This case describes a novel variant in DVL1 identified in a fetus with prenatal and postnatal phenotypic features consistent with ADRS. To our knowledge, this is the first reported case of a prenatal molecular diagnosis of the dominant form of Robinow syndrome and the third case to describe prenatal ultrasound findings associated with this diagnosis.

  View details for DOI 10.1002/pd.6632

  View details for PubMedID 38982229

• Newborn Screening for X-Linked Adrenoleukodystrophy (X-ALD): Biochemical, Molecular, and Clinical Characteristics of Other Genetic Conditions. Genes Mares Beltran, C. F., Tise, C. G., Barrick, R., Niehaus, A. D., Sponberg, R., Chang, R., Enns, G. M., Abdenur, J. E. 2024; 15 (7)

  Abstract

  The state of California (CA) added X-linked adrenoleukodystrophy (X-ALD) to newborn screening (NBS) in 2016 via the measurement of C26:0-lysophosphatidylcholine (C26:0-LPC) in a two-tier fashion, followed by sequencing of the ABCD1 gene. This has resulted in the identification of individuals with genetic conditions beyond X-ALD that can also result in elevated C26:0-LPC by NBS. We describe the biochemical, molecular, and clinical characteristics of nine patients from two metabolic centers in California who screened positive by NBS for elevated C26:0-LPC between 2016 and 2022 and were ultimately diagnosed with a genetic condition other than X-ALD. Seven individuals were diagnosed with Zellweger spectrum disorder (ZSD) due to biallelic variants in PEX genes. One male was diagnosed with Klinefelter syndrome and one female was found to have an X chromosome contiguous gene deletion syndrome after the identification of a heterozygous VUS and hemizygous VUS variant in ABCD1, respectively. Patients with ZSD had significantly higher first- and second-tier C26:0-LPC levels compared to the two non-ZSD cases. Identification of children with ZSD and atypical patterns of ABCD1 variants is a secondary benefit of NBS for X-ALD, leading to earlier diagnosis, prompt therapeutic initiation, and more accurate genetic counseling. As screening for X-ALD continues via the measurement of C26:0-LPC, our knowledge of additional genetic conditions associated with elevated C26:0-LPC will continue to advance, allowing for increased recognition of other genetic disorders for which early intervention is warranted.

  View details for DOI 10.3390/genes15070838

  View details for PubMedID 39062617

  View details for PubMedCentralID PMC11275617

• Decoding the Mystery of Recurrent Pregnancy Loss: Revelations from Genome Sequencing. Aminbeidokhti, M., Nagasuri, A., Cakmak, H., Jaswa, E., Baldwin, M., Edelman, A., Pollard, E., Snyder, M., Sirota, M., Tise, C., Bernstein, J., Stephenson, M., Lathi, R., Yatsenko, S., Rajkovic, A. SPRINGER HEIDELBERG. 2024: 76A

  View details for Web of Science ID 001287525000057

• Monozygotic twins discordant for a congenital cranial dysinnervation disorder with features of Moebius syndrome. American journal of medical genetics. Part A Gates, R. W., Webb, B. D., Stevenson, D. A., Jabs, E. W., DeFilippo, C., Ruzhnikov, M. R., Tise, C. G. 2023

  Abstract

  Moebius syndrome is a congenital cranial dysinnervation disorder (CCDD) that presents with nonprogressive cranial nerve (CN) VI and VII palsies resulting in facial weakness and inability to abduct the eye(s). While many CCDDs have an underlying genetic cause, the etiology of Moebius syndrome remains unclear as most cases are sporadic. Here, we describe a pair of monochorionic, diamniotic twin girls; one with normal growth and development, and one with micrognathia, reduced facial expression, and poor feeding. Magnetic resonance imaging of the brain performed on the affected twin at 19 months of age showed severely hypoplastic or absent CN IV bilaterally, left CN VI smaller than right, and bilateral hypoplastic CN VII and IX, consistent with a diagnosis of a CCDD, most similar to that of Moebius syndrome. Genomic sequencing was performed on each twin and data was assessed for discordant variants, as well as variants in novel and CCDD-associated genes. No pathogenic, likely pathogenic, or variants of uncertain significance were identified in genes known to be associated with CCDDs or other congenital facial weakness conditions. This family provides further evidence in favor of a stochastic event as the etiology in Moebius syndrome, rather than a monogenic condition.

  View details for DOI 10.1002/ajmg.a.63389

  View details for PubMedID 37675855

• A homozygous Gly470Ala variant in PEX6 causes severe Zellweger spectrum disorder. American journal of medical genetics. Part A Galarreta, C. I., Wong, K., Carmichael, J., Woods, J., Tise, C. G., Niehaus, A. D., Schildt, A. J., Verscaj, C. P., Cusmano-Ozog, K. P. 2023

  Abstract

  Zellweger spectrum disorder (ZSD) is a group of autosomal recessive disorders caused by biallelic pathogenic variants in any one of the 13 PEX genes essential for peroxisomal biogenesis. We report a cohort of nine infants who presented at birth with severe neonatal features suggestive of ZSD and found to be homozygous for a variant in PEX6 (NM_000287.4:c.1409G > C[p.Gly470Ala]). All were of Mixtec ancestry and identified by the California Newborn Screening (NBS) Program to have elevated C26:0-lysophosphatidylcholine but no reportable variants in ABCD1. The clinical and biochemical features of this cohort are described within. Gly470Ala may represent a founder variant in the Mixtec population of Central California. ZSD should be considered in patients who present at birth with severe hypotonia and enlarged fontanelles, especially in the setting of an abnormal NBS, Mixtec ancestry, or family history of infant death. There is a need to further characterize the natural history of ZSD, the Gly470Ala variant, and expand upon possible genotype-phenotype correlations.

  View details for DOI 10.1002/ajmg.a.63234

  View details for PubMedID 37144748

• BIOCHEMICAL, MOLECULAR, AND CLINICAL CHARACTERISTICS OF PEROXISOMAL DISORDERS DETECTED BY CALIFORNIA NEWBORN SCREENING (NBS) PROGRAM Beltran, C., Abdenur, J., Chang, R., Barrick, R., Spongberg, R., Tise, C. G., Niehaus, A. D., Enns, G. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2023: 72

  View details for DOI 10.1016/j.ymgme.2023.107455

  View details for Web of Science ID 001175367500082

• Creatine Transporter Deficiency Presenting as Failure to Thrive: A Case Report of a Novel SLC6A8 Variant Causing a Treatable but Likely Underdiagnosed Genetic Disorder. Journal of investigative medicine high impact case reports Tise, C. G., Palma, M. J., Cusmano-Ozog, K. P., Matalon, D. R. 2023; 11: 23247096231154438

  Abstract

  Cerebral creatine deficiency syndromes (CCDS) are a rare group of inherited metabolic disorders (IMDs) that often present with nonspecific findings including global developmental delay (GDD), intellectual disability (ID), seizures, hypotonia, and behavioral differences. Creatine transporter (CRTR) deficiency is the most common CCDS, exhibiting X-linked inheritance and an estimated prevalence as high as 2.6% in individuals with neurodevelopmental disorders. Here, we present a 20-month-old boy with worsening failure to thrive (FTT) and GDD admitted for evaluation. He was found to have persistently low serum creatinine levels and a family history notable for a mother with learning disabilities and a maternal male cousin with GDD. Urine analyses revealed a marked elevation of creatine and elevated creatine:creatinine ratio suggestive of CRTR deficiency. Molecular genetic testing of SLC6A8 identified a maternally inherited hemizygous variant and brain magnetic resonance spectroscopy (MRS) showed diffusely diminished creatine peaks, further supporting the diagnosis of CRTR deficiency. The proband was started on creatine, arginine, and glycine supplementation and has demonstrated improved development. This case highlights that CRTR deficiency should be considered in all patients presenting with FTT and abnormal neurodevelopmental features, particularly if creatinine levels are low on serum chemistry studies. The nonspecific presentation of this condition in males and females likely has resulted in CRTR deficiency being underdiagnosed. There are existing therapies for individuals affected with CRTR deficiency and other CCDS, highlighting the importance of early diagnosis and intervention for affected individuals.

  View details for DOI 10.1177/23247096231154438

  View details for PubMedID 36752093

• Recent tPA administration can cause pseudo-hyperargininemia and may mimic arginase deficiency or arginine supplementation. JIMD reports Cusmano-Ozog, K. P., Renck, A. K., Tise, C. G. 2022; 63 (6): 563-567

  Abstract

  Individuals suspected of or diagnosed with a rare disorder, including inherited metabolic disorders (IMD), often need frequent and/or urgent vascular access for blood draws and treatment, making central indwelling catheters commonly used devices in this patient population. These indwelling catheters are prone to thrombosis, limiting vascular access. This complication is frequently resolved with the use of altepase, a recombinant tissue plasminogen activator (tPA). This report describes two individuals, one with a known IMD and one undergoing evaluation for an IMD, who were found to have hyperargininemia (>500 muM; reference 10-140 muM) by plasma amino acid (PAA) analysis of a specimen collected ~1.5-3 h after clearance of an indwelling catheter with tPA. In both cases, hyperargininemia resolved with repeat testing, suggesting pseudo-hyperargininemia secondary to tPA administration. Quantitative amino acid analysis of the administered tPA demonstrated an arginine level of ~200mM, supporting tPA as the cause of pseudo-hyperargininemia. Certain formulations of tPA contain high concentrations of arginine, which if not cleared properly can result in marked elevations of arginine, mimicking arginase deficiency or suggesting arginine supplementation. Thus, the possibility of pseudohyperargininemia due to tPA administration should be considered when obtaining PAAs from an indwelling catheter in any individual being evaluated or managed for an IMD.

  View details for DOI 10.1002/jmd2.12328

  View details for PubMedID 36341162

• Short Bones, Renal Stones, and Diagnostic Moans: Hypercalcemia in a Girl Found to Have Coffin-Lowry Syndrome. Journal of investigative medicine high impact case reports Tise, C. G., Matalon, D. R., Manning, M. A., Byers, H. M., Grover, M. 2022; 10: 23247096221101844

  Abstract

  Pathogenic variants in RPS6KA3 are associated with Coffin-Lowry syndrome (CLS), an X-linked semidominant disorder characterized by intellectual disability, stimulus-induced drop attacks, distinctive facial features, progressive kyphoscoliosis, and digit anomalies in hemizygous males. Heterozygous females may also have features of CLS; however, there can be considerable phenotypic variation, often attributed to ratios of X-inactivation in various tissue types. Although skeletal anomalies and short stature are hallmarks of CLS, hypercalcemia has not been reported. Here we describe a 30-month-old girl with gross motor delays, short stature, dysmorphic features, bilateral duplicated renal collecting systems, and no family history of hypercalcemia who required multiple admissions for idiopathic hypercalcemia necessitating bisphosphonate infusions at 12.5 and 15 months of age. A maternally inherited likely-pathogenic variant in RPS6KA3 was identified by trio exome sequencing, consistent with the diagnosis of CLS in the proband and her mother. Maternal history was notable only for decreased height compared to first-degree relatives, bilateral genu valgum, and a bicornuate uterus; she was later found to also have a partially duplicated left renal collecting system. Subsequent X-inactivation studies in blood aligned with the phenotypic variation between mother and daughter. Although hypercalcemia is not a reported feature in CLS, there is evidence of interrupted osteoblast differentiation, providing a potential mechanism for hypercalcemia in this genetic condition. The hypercalcemia in this case may represent a severe presentation of an unrecognized clinical feature in CLS that resolves with age. This case further highlights the intrafamilial phenotypic variation of CLS among females, suggesting X-inactivation as the underlying mechanism, and demonstrates the value of exome sequencing in patients for whom a genetic disorder is highly suspected but not identified despite thorough evaluation.

  View details for DOI 10.1177/23247096221101844

  View details for PubMedID 35638718

• SUCCESSFUL CARDIAC TRANSPLANTATION AND LONG-TERM FOLLOW-UP IN DNAJC19-ASSOCIATED DILATED CARDIOMYOPATHY WITH ATAXIA Tahata, S., Tise, C., Floyd, B., Cusmano-Ozog, K., Ruzhnikov, M., Enns, G. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2022: 302

  View details for Web of Science ID 000772339900104

• MITOCHONDRIAL-ATP6-ASSOCIATED DISEASE PRESENTS WITH DISTINCT PATTERN ON NEWBORN SCREENING: SHOULD IT BE INCLUDED AS A SECONDARY CONDITION? Tise, C., Mendelsohn, B., Lee, C., Woods, J., Hall, P., Tang, H., Rinaldo, P., Cowan, T., Cusmano-Ozog, K. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2022: 247-248

  View details for Web of Science ID 000772339900011

• Biochem for the Win! The added value of biochemical genetic testing for diagnosis and variant interpretation in the genomic era Tise, C., Grand, K., Corado, J., Gates, R., Graham, J., Enns, G., Gomez-Ospina, N., Mak, J., Cowan, T., Cusmano-Ozog, K. ELSEVIER SCIENCE INC. 2022: S24

  View details for DOI 10.1016/j.gim.2022.01.075

  View details for Web of Science ID 000788465500037

• Clinical characterization of a new individual with mild SC4MOL deficiency: diagnostic and therapeutic implications JOURNAL OF TRANSLATIONAL GENETICS AND GENOMICS Morales, J., Curry, C. J., Tise, C. G., Kratz, L., Enns, G. M. 2022; 6 (2): 257-265

  View details for DOI 10.20517/jtgg.2022.01

  View details for Web of Science ID 001208119200008

• Profound neonatal lactic acidosis and renal tubulopathy in a patient with glycogen storage disease type IXɑ2 secondary to a de novo pathogenic variant in PHKA2. Molecular genetics and metabolism reports Morales, J. A., Tise, C. G., Narang, A., Grimm, P. C., Enns, G. M., Lee, C. U. 2021; 27: 100765

  Abstract

  The phenotype of individuals with glycogen storage disease (GSD) IX appears to be highly variable, even within subtypes. Features include short stature, fasting hypoglycemia with ketosis, hepatomegaly, and transaminitis. GSD IXɑ2 is caused by hemizygous pathogenic variants in PHKA2, and results in deficiency of the phosphorylase kinase enzyme, particularly in the liver. Like other GSDs, GSD IXɑ2 can present with hypoglycemia and post-prandial lactic acidosis, but has never been reported in a newborn, nor with lactic acidosis as the presenting feature. Here we describe the clinical presentation and course of a newborn boy with profound neonatal lactic and metabolic acidosis, renal tubulopathy, and sensorineural hearing loss (SNHL) diagnosed with GSD IXɑ2 through exome sequencing. Review of the literature suggests this case represents an atypical and severe presentation of GSD IXɑ2 and proposes expansion of the phenotype to include neonatal lactic acidosis and renal tubulopathy.

  View details for DOI 10.1016/j.ymgmr.2021.100765

  View details for PubMedID 34277355

  View details for PubMedCentralID PMC8261893

• Case 1: Rapidly Rising Bilirubin Level in a 3-day-old Term Infant. NeoReviews Tise, C. G., Joshi, N. S., Erice-Taganas, A. D., Blecharczyk, E. M. 2020; 21 (10): e687–e690

  View details for DOI 10.1542/neo.21-10-e687

  View details for PubMedID 33004562

• nonsense variants on DHEA homeostasis. Molecular genetics and metabolism reports Tise, C. G., Anforth, L. E., Zhou, A. E., Perry, J. A., McArdle, P. F., Streeten, E. A., Shuldiner, A. R., Yerges-Armstrong, L. M. 2017; 10: 84-91

  Abstract

  Sulfate is critical in the biotransformation of multiple compounds via sulfation. These compounds include neurotransmitters, proteoglycans, xenobiotics, and hormones such as dehydroepiandrosterone (DHEA). Sulfation reactions are thought to be rate-limited by endogenous sulfate concentrations. The gene, SLC13A1, encodes the sodium-sulfate cotransporter NaS1, responsible for sulfate (re)absorption in the intestines and kidneys. We previously reported two rare, non-linked, nonsense variants in SLC13A1 (R12X and W48X) associated with hyposulfatemia (P = 9 × 10- 20).To examine the effect of serum sulfate concentration and sulfate-lowering genotype on DHEA homeostasis.Retrospective cohort study.Academic research.Participants of the Amish Pharmacogenomics of Anti-Platelet Intervention (PAPI) Study and the Amish Hereditary and Phenotype Intervention (HAPI) Study.DHEA, DHEA-S, and DHEA-S/DHEA ratio.Increased serum sulfate was associated with decreased DHEA-S (P = 0.03) and DHEA-S/DHEA ratio (P = 0.06) in males but not females. Female SLC13A1 nonsense variant carriers, who had lower serum sulfate (P = 9 × 10- 13 ), exhibited 14% lower DHEA levels (P = 0.01) and 7% higher DHEA-S/DHEA ratios compared to female non-carriers (P = 0.002). Consistent with this finding, female SLC13A1 nonsense variant carriers also had lower total testosterone levels compared to non-carrier females (P = 0.03).Our results demonstrate an inverse relationship between serum sulfate, and DHEA-S and DHEA-S/DHEA ratio in men, while also suggesting that the sulfate-lowering variants, SLC13A1 R12X and W48X, decrease DHEA and testosterone levels, and increase DHEA-S/DHEA ratio in women. While paradoxical, these results illustrate the complexity of the mechanisms involved in DHEA homeostasis and warrant additional studies to better understand sulfate's role in hormone physiology.

  View details for DOI 10.1016/j.ymgmr.2017.01.005

  View details for PubMedID 28154797

  View details for PubMedCentralID PMC5278115

• Are Patients with Psychogenic Movement Disorders More Likely to be Healthcare Workers? MOVEMENT DISORDERS CLINICAL PRACTICE Perry, C. G., Holmes, K. G., Gruber-Baldini, A. L., Anderson, K. E., Shulman, L. M., Weiner, W. J., Reich, S. G. 2017; 4 (1): 62–67

  View details for DOI 10.1002/mdc3.12351

  View details for Web of Science ID 000396370400014

• Educational Innovations in Clinical Pharmacogenomics CLINICAL PHARMACOLOGY & THERAPEUTICS Perry, C. G., Maloney, K. A., Beitelshees, A. L., Jeng, L. J., Ambulos, N. P., Shuldiner, A. R., Blitzer, M. G. 2016; 99 (6): 582-584

  Abstract

  Genetic and genomic discovery is revolutionizing medicine at an extraordinary pace, leading to a better understanding of disease and improved treatments for patients. This advanced pace of discovery presents an urgency to expand medical school curricula to include genetic and genomic testing (including pharmacogenomics), and integration of genomic medicine into clinical practice. Consequently, organizations and healthcare authorities have charged medical schools with training future physicians to be competent in their knowledge of genomic implementation.

  View details for DOI 10.1002/cpt.352

  View details for Web of Science ID 000376246600016

  View details for PubMedID 26875057

• Pharmacometabolomics reveals that serotonin is implicated in aspirin response variability. CPT: pharmacometrics & systems pharmacology Ellero-Simatos, S., Lewis, J. P., Georgiades, A., Yerges-Armstrong, L. M., Beitelshees, A. L., Horenstein, R. B., Dane, A., Harms, A. C., Ramaker, R., Vreeken, R. J., Perry, C. G., Zhu, H., Sànchez, C. L., Kuhn, C., Ortel, T. L., Shuldiner, A. R., Hankemeier, T., Kaddurah-Daouk, R. 2014; 3

  Abstract

  While aspirin is generally effective for prevention of cardiovascular disease, considerable variation in drug response exists, resulting in some individuals displaying high on-treatment platelet reactivity. We used pharmacometabolomics to define pathways implicated in variation of response to treatment. We profiled serum samples from healthy subjects pre- and postaspirin (14 days, 81 mg/day) using mass spectrometry. We established a strong signature of aspirin exposure independent of response (15/34 metabolites changed). In our discovery (N = 80) and replication (N = 125) cohorts, higher serotonin levels pre- and postaspirin correlated with high, postaspirin, collagen-induced platelet aggregation. In a third cohort, platelets from subjects with the highest levels of serotonin preaspirin retained higher reactivity after incubation with aspirin than platelets from subjects with the lowest serotonin levels preaspirin (72 ± 8 vs. 61 ± 11%, P = 0.02, N = 20). Finally, ex vivo, serotonin strongly increased platelet reactivity after platelet incubation with aspirin (+20%, P = 4.9 × 10(-4), N = 12). These results suggest that serotonin is implicated in aspirin response variability.

  View details for DOI 10.1038/psp.2014.22

  View details for PubMedID 25029353

  View details for PubMedCentralID PMC4120016

• Pharmacogenomics of Anti-platelet and Anti-coagulation Therapy CURRENT CARDIOLOGY REPORTS Fisch, A. S., Perry, C. G., Stephens, S. H., Horenstein, R. B., Shuldiner, A. R. 2013; 15 (7)

  Abstract

  Arterial thrombosis is a major component of vascular disease, especially myocardial infarction (MI) and stroke. Current anti-thrombotic therapies such as warfarin and clopidogrel are effective in inhibiting cardiovascular events; however, there is great inter-individual variability in response to these medications. In recent years, it has been recognized that genetic factors play a significant role in drug response, and, subsequently, common variants in genes responsible for metabolism and drug action have been identified. These discoveries along with new diagnostic targets and therapeutic strategies hold promise for more effective individualized anti-coagulation and anti-platelet therapy.

  View details for DOI 10.1007/s11886-013-0381-3

  View details for Web of Science ID 000345083100009

  View details for PubMedID 23797323

  View details for PubMedCentralID PMC3809070

• Pharmacogenomics of anti-platelet therapy: how much evidence is enough for clinical implementation? JOURNAL OF HUMAN GENETICS Perry, C. G., Shuldiner, A. R. 2013; 58 (6): 339-345

  Abstract

  Pharmacogenomics, the study of the genomics of drug response and adverse effects, holds great promise for more effective individualized (personalized) medicine. Recent evidence supports a role of loss-of-function (LOF) variants in the cytochrome P450 enzyme CYP2C19 as a determinant of clopidogrel response. Patients given clopidogrel after percutaneous coronary intervention who carry LOF variants do not metabolize clopidogrel, a prodrug, into its active form resulting in decreased inhibition of platelet function and a higher likelihood of recurrent cardiovascular events. Despite a large body of evidence supporting clinical utility, adoption of anti-platelet pharmacogenetics into clinical practice has been slow. In this review, we summarize the pharmacokinetic, pharmacodynamic and clinical evidence, identify gaps in knowledge and other barriers that appear to be slowing adoption, and describe CYP2C19 pharmacogenetics implementation projects currently underway. Only when we surmount these barriers will clinicians be able to use pharmacogenetic information in conjunction with the history, physical examination and other medical tests and information to choose the most efficacious anti-platelet therapy for each individual patient.

  View details for DOI 10.1038/jhg.2013.41

  View details for Web of Science ID 000320843600007

  View details for PubMedID 23697979

  View details for PubMedCentralID PMC3715315