Andrea Hanson-Kahn

All Publications

• Xq22 deletions and correlation with distinct neurological disease traits in females: further evidence for a contiguous gene syndrome. Human mutation Hijazi, H., Coelho, F. S., Gonzaga-Jauregui, C., Bernardini, L., Mar, S. S., Manning, M. A., Hanson-Kahn, A., Naidu, S., Srivastava, S., Lee, J. A., Jones, J. R., Friez, M. J., Alberico, T., Torres, B., Fang, P., Cheung, S. W., Song, X., Davis-Williams, A., Jornlin, C., Wight, P. A., Patyal, P., Taube, J., Poretti, A., Inoue, K., Zhang, F., Pehlivan, D., Carvalho, C. M., Hobson, G. M., Lupski, J. R. 2019

  Abstract

  Xq22 deletions that encompass PLP1 (Xq22-PLP1-DEL) are notable for variable expressivity of neurological disease traits in females ranging from a mild late-onset form of Spastic Paraplegia type 2 [MIM# 312920], sometimes associated with skewed X-inactivation, to an early-onset neurological disease trait (EONDT) of severe developmental delay, intellectual disability and behavioral abnormalities. Size and gene content of Xq22-PLP1-DEL vary and were proposed as potential molecular etiologies underlying variable expressivity in carrier females where two smallest regions of overlap (SROs) were suggested to influence disease. We ascertained a cohort of eight unrelated patients harboring Xq22-PLP1-DEL and performed high-density array Comparative Genomic Hybridization (aCGH) and breakpoint-junction sequencing. Molecular characterization of Xq22-PLP1-DEL from 17 cases (8 herein and 9 published) revealed an overrepresentation of breakpoints that reside within repeats (11/17, ~65%) and the clustering of ~47% of proximal breakpoints in a genomic instability hotspot with characteristic non-B DNA density. These findings implicate a potential role for genomic architecture in stimulating the formation of Xq22-PLP1-DEL. The correlation of Xq22-PLP1-DEL gene content with neurological disease trait in female cases enabled refinement of the associated SROs to a single genomic interval containing six genes. Our data support the hypothesis that genes contiguous to PLP1 contribute to EONDT. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/humu.23902

  View details for PubMedID 31448840

• Understanding variants of uncertain significance in the era of multigene panels: Through the eyes of the patient JOURNAL OF GENETIC COUNSELING Reuter, C., Chun, N., Pariani, M., Hanson-Kahn, A. 2019; 28 (4): 878–86

  View details for DOI 10.1002/jgc4.1130

  View details for Web of Science ID 000482136400016

• Use of genetic risks in pediatric organ transplantation listing decisions: A national survey PEDIATRIC TRANSPLANTATION Graf, M., Char, D., Hanson-Kahn, A., Magnus, D. 2019; 23 (4)

  View details for DOI 10.1111/petr.13402

  View details for Web of Science ID 000470844700003

• Use of genetic risks in pediatric organ transplantation listing decisions: A national survey. Pediatric transplantation Graf, M., Char, D., Hanson-Kahn, A., Magnus, D. 2019: e13402

  Abstract

  There is a limited supply of organs for all those who need them for survival. Thus, careful decisions must be made about who is listed for transplant. Studies show that manifesting genetic disease can impact listing eligibility. What has not yet been studied is the impact genetic risks for future disease have on a patient's chance to be listed. Surveys were emailed to 163 pediatric liver, heart, and kidney transplant programs across the United States to elicit views and experiences of key clinicians regarding each program's use of genetic risks (ie, predispositions, positive predictive testing) in listing decisions. Response rate was 42%. Sixty-four percent of programs have required genetic testing for specific indications prior to listing decisions. Sixteen percent have required it without specific indications, suggesting that genetic testing may be used to screen candidates. Six percent have chosen not to list patients with secondary findings or family histories of genetic conditions. In hypothetical scenarios, programs consider cancer predispositions and adult-onset neurological conditions to be relative contraindications to listing (61%, 17%, and 8% depending on scenario), and some consider them absolute contraindications (5% and 3% depending on scenario). Only 3% of programs have formal policies for these scenarios, but all consult genetic specialists at least "sometimes" for results interpretation. Our study reveals that pediatric transplant programs are using future onset genetic risks in listing decisions. As genetic testing is increasingly adopted into pediatric medicine, further study is needed to prevent possible inappropriate use of genetic information from impacting listing eligibility.

  View details for PubMedID 31012250

• Developing a genomics rotation: Practical training around variant interpretation for genetic counseling students JOURNAL OF GENETIC COUNSELING Grove, M. E., White, S., Fisk, D. G., Rego, S., Dagan-Rosenfeld, O., Kohler, J. N., Reuter, C. M., Bonner, D., Wheeler, M. T., Bernstein, J. A., Ormond, K. E., Hanson-Kahn, A. K., Undiagnosed Dis Network 2019; 28 (2): 466–76

  View details for DOI 10.1002/jgc4.1094

  View details for Web of Science ID 000463993600030

• Developing a genomics rotation: Practical training around variant interpretation for genetic counseling students. Journal of genetic counseling Grove, M. E., White, S. n., Fisk, D. G., Rego, S. n., Dagan-Rosenfeld, O. n., Kohler, J. N., Reuter, C. M., Bonner, D. n., Wheeler, M. T., Bernstein, J. A., Ormond, K. E., Hanson-Kahn, A. K. 2019

  Abstract

  With the wide adoption of next-generation sequencing (NGS)-based genetic tests, genetic counselors require increased familiarity with NGS technology, variant interpretation concepts, and variant assessment tools. The use of exome and genome sequencing in clinical care has expanded the reach and diversity of genetic testing. Regardless of the setting where genetic counselors are performing variant interpretation or reporting, most of them have learned these skills from colleagues, while on the job. Though traditional, lecture-based learning around these topics is important, there has been growing need for the inclusion of case-based, experiential training of genomics and variant interpretation for genetic counseling students, with the goal of creating a strong foundation in variant interpretation for new genetic counselors, regardless of what area of practice they enter. To address this need, we established a genomics and variant interpretation rotation for Stanford's genetic counseling training program. In response to changes in the genomics landscape, this has now evolved into three unique rotation experiences, each focused on variant interpretation in the context of various genomic settings, including clinical laboratory, research laboratory, and healthy genomic analysis studies. Here, we describe the goals and learning objectives that we have developed for these variant interpretation rotations, and illustrate how these concepts are applied in practice.

  View details for PubMedID 30706981

• Positive Attitudes and Therapeutic Misconception Around Hypothetical Clinical Trial Participation in the Huntington's Disease Community. Journal of Huntington's disease Cotter, K. n., Siskind, C. n., Sha, S. n., Hanson-Kahn, A. n. 2019

  Abstract

  New therapies that could modify the disease course of Huntington's disease (HD) are entering clinical trials. However, conceptions about clinical research from the HD community are unknown. This knowledge could help inform patient-clinician discussions surrounding clinical trial participation.The purpose of this study was to assess clinical trial attitudes and understanding in the HD community.We developed a survey incorporating two measures of trial understanding and attitudes and the impact of therapeutic route of administration on hypothetical trial participation. The survey was distributed via emails, flyers, and social media through HD-related organizations.There were 73 responses. Individuals self-reported as clinically diagnosed with HD, gene positive but asymptomatic, or primary caregivers. Respondents viewed clinical trials positively and generally viewed trials as safe. Individuals with prior HD-related research experience were less likely to have negative expectations about trials than those without research experience (p = 0.002), and women had higher information needs than men (p = 0.001) Individuals with HD were more likely than the other groups to experience therapeutic misconception (p = 0.002). All respondents were able to appraise risks and benefits of research but exhibited optimism about trial outcomes. Willingness to participate was highest when the route of administration was minimally invasive.While the HD community views clinical trials positively, patients with HD are at high risk for therapeutic misconception and all groups are optimistic about trial outcomes. Limitations of this study include a small sample that may be inclined to view research positively given past trial participation and interest in participating in HD surveys. However, the findings from this study can be used to strengthen informed consent during HD clinical trial recruitment.

  View details for DOI 10.3233/JHD-190382

  View details for PubMedID 31594242

• Understanding variants of uncertain significance in the era of multigene panels: Through the eyes of the patient. Journal of genetic counseling Reuter, C. n., Chun, N. n., Pariani, M. n., Hanson-Kahn, A. n. 2019

  Abstract

  Variants of uncertain significance (VUSs) are often disclosed to patients despite ambiguous association with disease risk and lack of clinical actionability. It is important to understand how patients understand a VUS result, but few studies have assessed this. Our qualitative study explored patient recall, reaction to, and interpretation of a VUS in the context of multigene panels. We conducted 11 semi-structured phone interviews with adults who had a VUS identified on multigene panel testing in a hereditary oncology clinic, with questions focusing on the VUS result, personal and family history, and motivations for and expectations of genetic testing. Transcripts were coded iteratively, using both deductive and inductive codes. Overall, participants usually recalled that they had a VUS, despite variation in the vocabulary used. Participants responded both emotionally and intellectually to receiving information about having a VUS, which was often a result of their expectations and motivations prior to testing. Overall, participants understood the lack of clinical significance of a VUS, yet often interpreted the etiologic significance of a VUS within the context of the personal and family history. Our study provides insight into a process by which patients translate uncertain genetic testing results into a construct that fits within their current belief framework and which may be facilitated by a genetic counselor.

  View details for PubMedID 31050105

• Autosomal recessive Stickler syndrome resulting from a COL9A3 mutation. American journal of medical genetics. Part A Hanson-Kahn, A., Li, B., Cohn, D. H., Nickerson, D. A., Bamshad, M. J., University of Washington Center for Mendelian Genomics, Hudgins, L. 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

• "This could be me": exploring the impact of genetic risk for Huntington's disease young caregivers. Journal of community genetics Dondanville, D. S., Hanson-Kahn, A. K., Kavanaugh, M. S., Siskind, C. E., Fanos, J. H. 2018

  Abstract

  Huntington's disease (HD) is a predominantly adult-onset, genetic, neurodegenerative condition. Children of affected individuals have a 50% risk of inheriting HD and often assume caregiving roles for their parent. Studies specifically focused on HD young caregivers have proposed that the genetic risk component of HD "exacerbates" the caregiving experience and identified common responsibilities, burdens, and support needs, but none have explored the relationship between the caregiving role and perception of genetic risk. In an attempt to understand this relationship, we conducted a qualitative study to explore the interaction between a young caregiver's perception of genetic risk, the caregiving experience, and thoughts about and plans for predictive testing. Thirteen individuals between 15 and 25years who provided care for a parent with HD were recruited from two HD youth groups and local support groups. Interviews were recorded, transcribed, and analyzed thematically. Two themes emerged: (1) caregiving and thoughts about risk and (2) caregiving and perceived opinions towards genetic testing. Our findings suggest that the genetic risk colors the caregiving experience by evoking feelings about the future and a potential diagnosis of HD, in addition to impacting plans for predictive testing. Genetic counselors can use these findings to inform their understanding of caregiver experiences, which can aid them when helping patients explore their motivations for testing during a genetic counseling session. Future studies should explore the extent to which health care providers acknowledge the work of young caregivers in the home and provide support to these individuals.

  View details for PubMedID 30430455

• Evolving Decisions: Perspectives of Active and Athletic Individuals with Inherited Heart Disease Who Exercise Against Recommendations. Journal of genetic counseling Subas, T., Luiten, R., Hanson-Kahn, A., Wheeler, M., Caleshu, C. 2018

  Abstract

  Individuals with hypertrophic cardiomyopathy (HCM) and long QT syndrome (LQTS) are advised to avoid certain forms of exercise to reduce their risk of sudden death. Cardiovascular genetic counselors facilitate both adaptation to, and decision-making about, these exercise recommendations. This study describes decision-making and experiences of active adults who exercise above physicians' recommendations. Purposive sampling was used to select adults with HCM and LQTS who self-identified as exercising above recommendations. Semi-structured interviews explored participants' decision-making and the psychological impact of exercise recommendations. Fifteen individuals were interviewed (HCM: 10; LQTS: 5; mean age: 40). Transcripts were coded and analyzed for underlying themes. Despite exercising above recommendations, nearly all participants made some modifications to their prior exercise regimen. Often these decisions changed over time, underscoring the importance of shared decision-making conversations beyond the initial evaluation. The importance of exercise was frequently cited as a reason for continued exercise, as were perceptions of sudden death risk as low, acceptable, or modifiable. Many participants reported that family and friends supported their exercise decisions, with a minority having family or friends that expressed significant reservations. Genetic counselors, cardiologists, and nurses can use these data to inform their counseling regarding exercise recommendations.

  View details for PubMedID 30220053

• De Novo Missense Variants in TRAF7 Cause Developmental Delay, Congenital Anomalies, and Dysmorphic Features. American journal of human genetics Tokita, M. J., Chen, C. A., Chitayat, D. n., Macnamara, E. n., Rosenfeld, J. A., Hanchard, N. n., Lewis, A. M., Brown, C. W., Marom, R. n., Shao, Y. n., Novacic, D. n., Wolfe, L. n., Wahl, C. n., Tifft, C. J., Toro, C. n., Bernstein, J. A., Hale, C. L., Silver, J. n., Hudgins, L. n., Ananth, A. n., Hanson-Kahn, A. n., Shuster, S. n., Magoulas, P. L., Patel, V. N., Zhu, W. n., Chen, S. M., Jiang, Y. n., Liu, P. n., Eng, C. M., Batkovskyte, D. n., di Ronza, A. n., Sardiello, M. n., Lee, B. H., Schaaf, C. P., Yang, Y. n., Wang, X. n. 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

• MACF1 Mutations Encoding Highly Conserved Zinc-Binding Residues of the GAR Domain Cause Defects in Neuronal Migration and Axon Guidance. American journal of human genetics Dobyns, W. B., Aldinger, K. A., Ishak, G. E., Mirzaa, G. M., Timms, A. E., Grout, M. E., Dremmen, M. H., Schot, R. n., Vandervore, L. n., van Slegtenhorst, M. A., Wilke, M. n., Kasteleijn, E. n., Lee, A. S., Barry, B. J., Chao, K. R., Szczałuba, K. n., Kobori, J. n., Hanson-Kahn, A. n., Bernstein, J. A., Carr, L. n., D'Arco, F. n., Miyana, K. n., Okazaki, T. n., Saito, Y. n., Sasaki, M. n., Das, S. n., Wheeler, M. M., Bamshad, M. J., Nickerson, D. A., Engle, E. C., Verheijen, F. W., Doherty, D. n., Mancini, G. M. 2018

  Abstract

  To date, mutations in 15 actin- or microtubule-associated genes have been associated with the cortical malformation lissencephaly and variable brainstem hypoplasia. During a multicenter review, we recognized a rare lissencephaly variant with a complex brainstem malformation in three unrelated children. We searched our large brain-malformation databases and found another five children with this malformation (as well as one with a less severe variant), analyzed available whole-exome or -genome sequencing data, and tested ciliogenesis in two affected individuals. The brain malformation comprised posterior predominant lissencephaly and midline crossing defects consisting of absent anterior commissure and a striking W-shaped brainstem malformation caused by small or absent pontine crossing fibers. We discovered heterozygous de novo missense variants or an in-frame deletion involving highly conserved zinc-binding residues within the GAR domain of MACF1 in the first eight subjects. We studied cilium formation and found a higher proportion of mutant cells with short cilia than of control cells with short cilia. A ninth child had similar lissencephaly but only subtle brainstem dysplasia associated with a heterozygous de novo missense variant in the spectrin repeat domain of MACF1. Thus, we report variants of the microtubule-binding GAR domain of MACF1 as the cause of a distinctive and most likely pathognomonic brain malformation. A gain-of-function or dominant-negative mechanism appears likely given that many heterozygous mutations leading to protein truncation are included in the ExAC Browser. However, three de novo variants in MACF1 have been observed in large schizophrenia cohorts.

  View details for DOI 10.1016/j.ajhg.2018.10.019

  View details for PubMedID 30471716

• Sleep Disturbances in Individuals With Phelan-McDermid Syndrome: Correlation With Caregivers' Sleep Quality and Daytime Functioning SLEEP Bro, D., O'Hara, R., Primeau, M., Hanson-Kahn, A., Hallmayer, J., Bernstein, J. A. 2017; 40 (2)

  Abstract

  The aims of this study were to document sleep disturbances in individuals with Phelan-McDermid syndrome (PMS), to assess whether these individuals had been evaluated for sleep disorders, and to examine relationships between the sleep behavior of these individuals and the sleep behavior and daytime functioning of their caregivers.Participants were 193 caregivers of individuals with PMS recruited by the Phelan-McDermid Syndrome Foundation. Data were collected through a survey comprising 2 questionnaires: the Children's Sleep Habits Questionnaire (CSHQ) and the Parents' Sleep Habits Questionnaire. Data were analyzed using multiple linear regression analyses, Pearson correlation analyses, and independent-samples t-tests.Ninety percent of individuals with PMS showed evidence of marked sleep disturbance based on caregiver responses to the CSHQ. However, only 22% of individuals had undergone a formal sleep assessment. Reported increased sleep disturbance in individuals with PMS was a statistically significant predictor of reported increased sleep disturbance and daytime sleepiness in their caregivers.Sleep disturbance may be present in a substantial proportion of individuals with PMS and is negatively associated with caregivers' well-being. However, most individuals with PMS have not been evaluated for sleep disorders. When properly diagnosed, many sleep disorders can be alleviated with intervention. Thus, routine screening for and evaluation of sleep disturbances in individuals with PMS may have long-term positive impacts on the well-being of these individuals and their caregivers.

  View details for DOI 10.1093/sleep/zsw062

  View details for PubMedID 28364490

• The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies. Nature genetics Redin, C., Brand, H., Collins, R. L., Kammin, T., Mitchell, E., Hodge, J. C., Hanscom, C., Pillalamarri, V., Seabra, C. M., Abbott, M., Abdul-Rahman, O. A., Aberg, E., Adley, R., Alcaraz-Estrada, S. L., Alkuraya, F. S., An, Y., Anderson, M., Antolik, C., Anyane-Yeboa, K., Atkin, J. F., Bartell, T., Bernstein, J. A., Beyer, E., Blumenthal, I., Bongers, E. M., Brilstra, E. H., Brown, C. W., Brüggenwirth, H. T., Callewaert, B., Chiang, C., Corning, K., Cox, H., Cuppen, E., Currall, B. B., Cushing, T., David, D., Deardorff, M. A., Dheedene, A., D'Hooghe, M., de Vries, B. B., Earl, D. L., Ferguson, H. L., Fisher, H., FitzPatrick, D. R., Gerrol, P., Giachino, D., Glessner, J. T., Gliem, T., Grady, M., Graham, B. H., Griffis, C., Gripp, K. W., Gropman, A. L., Hanson-Kahn, A., Harris, D. J., Hayden, M. A., Hill, R., Hochstenbach, R., Hoffman, J. D., Hopkin, R. J., Hubshman, M. W., Innes, A. M., Irons, M., Irving, M., Jacobsen, J. C., Janssens, S., Jewett, T., Johnson, J. P., Jongmans, M. C., Kahler, S. G., Koolen, D. A., Korzelius, J., Kroisel, P. M., Lacassie, Y., Lawless, W., Lemyre, E., Leppig, K., Levin, A. V., Li, H., Li, H., Liao, E. C., Lim, C., Lose, E. J., Lucente, D., Macera, M. J., Manavalan, P., Mandrile, G., Marcelis, C. L., Margolin, L., Mason, T., Masser-Frye, D., McClellan, M. W., Mendoza, C. J., Menten, B., Middelkamp, S., Mikami, L. R., Moe, E., Mohammed, S., Mononen, T., Mortenson, M. E., Moya, G., Nieuwint, A. W., Ordulu, Z., Parkash, S., Pauker, S. P., Pereira, S., Perrin, D., Phelan, K., Aguilar, R. E., Poddighe, P. J., Pregno, G., Raskin, S., Reis, L., Rhead, W., Rita, D., Renkens, I., Roelens, F., Ruliera, J., Rump, P., Schilit, S. L., Shaheen, R., Sparkes, R., Spiegel, E., Stevens, B., Stone, M. R., Tagoe, J., Thakuria, J. V., van Bon, B. W., van de Kamp, J., van der Burgt, I., van Essen, T., van Ravenswaaij-Arts, C. M., van Roosmalen, M. J., Vergult, S., Volker-Touw, C. M., Warburton, D. P., Waterman, M. J., Wiley, S., Wilson, A., Yerena-de Vega, M. d., Zori, R. T., Levy, B., Brunner, H. G., de Leeuw, N., Kloosterman, W. P., Thorland, E. C., Morton, C. C., Gusella, J. F., Talkowski, M. E. 2017; 49 (1): 36-45

  Abstract

  Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. We propose that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements and provides insight into new pathogenic mechanisms, such as altered regulation due to changes in chromosome topology.

  View details for DOI 10.1038/ng.3720

  View details for PubMedID 27841880

• FOXP1-related intellectual disability syndrome: a recognisable entity. Journal of medical genetics Meerschaut, I. n., Rochefort, D. n., Revençu, N. n., Pètre, J. n., Corsello, C. n., Rouleau, G. A., Hamdan, F. F., Michaud, J. L., Morton, J. n., Radley, J. n., Ragge, N. n., García-Miñaúr, S. n., Lapunzina, P. n., Bralo, M. P., Mori, M. Á., Moortgat, S. n., Benoit, V. n., Mary, S. n., Bockaert, N. n., Oostra, A. n., Vanakker, O. n., Velinov, M. n., de Ravel, T. J., Mekahli, D. n., Sebat, J. n., Vaux, K. K., DiDonato, N. n., Hanson-Kahn, A. K., Hudgins, L. n., Dallapiccola, B. n., Novelli, A. n., Tarani, L. n., Andrieux, J. n., Parker, M. J., Neas, K. n., Ceulemans, B. n., Schoonjans, A. S., Prchalova, D. n., Havlovicova, M. n., Hancarova, M. n., Budisteanu, M. n., Dheedene, A. n., Menten, B. n., Dion, P. A., Lederer, D. n., Callewaert, B. n. 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

• Germline Loss-of-Function Mutations in EPHB4 Cause a Second Form of Capillary Malformation-Arteriovenous Malformation (CM-AVM2) Deregulating RAS-MAPK Signaling. Circulation Amyere, M. n., Revencu, N. n., Helaers, R. n., Pairet, E. n., Baselga, E. n., Cordisco, M. R., Chung, W. K., Dubois, J. n., Lacour, J. P., Martorell, L. n., Mazereeuw-Hautier, J. n., Pyeritz, R. E., Amor, D. J., Bisdorff, A. n., Blei, F. n., Bombei, H. n., Dompmartin, A. n., Brooks, D. G., Dupont, J. n., González-Enseñat, M. A., Frieden, I. J., Gérard, M. n., Kvarnung, M. n., Hanson-Kahn, A. K., Hudgins, L. n., Léauté-Labrèze, C. n., McCuaig, C. n., Metry, D. n., Parent, P. n., Paul, C. n., Petit, F. n., Phan, A. n., Quéré, I. n., Salhi, A. n., Turner, A. M., Vabres, P. n., Vicente, A. n., Wargon, O. n., Watanabe, S. n., Weibel, L. n., Wilson, A. n., Willing, M. n., Mulliken, J. B., Boon, L. M., Vikkula, M. n. 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

• The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies NATURE GENETICS Redin, C., Brand, H., Collins, R. L., Kammin, T., Mitchell, E., Hodge, J. C., Hanscom, C., Pillalamarri, V., Seabra, C. M., Abbott, M., Abdul-Rahman, O. A., Aberg, E., Adley, R., Alcaraz-Estrada, S. L., Alkuraya, F. S., An, Y., Anderson, M., Antolik, C., Anyane-Yeboa, K., Atkin, J. F., Bartell, T., Bernstein, J. A., Beyer, E., Blumenthal, I., Bongers, E. M., Brilstra, E. H., Brown, C. W., Bruggenwirth, H. T., Callewaert, B., Chiang, C., Corning, K., Cox, H., Cuppen, E., Currall, B. B., Cushing, T., David, D., Deardorff, M. A., Dheedene, A., D'Hooghe, M., de Vries, B. B., Earl, D. L., Ferguson, H. L., Fisher, H., FitzPatrick, D. R., Gerrol, P., Giachino, D., Glessner, J. T., Gliem, T., Grady, M., Graham, B. H., Griffis, C., Gripp, K. W., Gropman, A. L., Hanson-Kahn, A., Harris, D. J., Hayden, M. A., Hill, R., Hochstenbach, R., Hoffman, J. D., Hopkin, R. J., Hubshman, M. W., Innes, A. M., Irons, M., Irving, M., Jacobsen, J. C., Janssens, S., Jewett, T., Johnson, J. P., Jongmans, M. C., Kahler, S. G., Koolen, D. A., Korzelius, J., Kroisel, P. M., Lacassie, Y., Lawless, W., Lemyre, E., Leppig, K., Levin, A. V., Li, H., Li, H., Liao, E. C., Lim, C., Lose, E. J., Lucente, D., Macera, M. J., Manavalan, P., Mandrile, G., Marcelis, C. L., Margolin, L., Mason, T., Masser-Frye, D., McClellan, M. W., Mendoza, C. J., Menten, B., Middelkamp, S., Mikami, L. R., Moe, E., Mohammed, S., Mononen, T., Mortenson, M. E., Moya, G., Nieuwint, A. W., Ordulu, Z., Parkash, S., Pauker, S. P., Pereira, S., Perrin, D., Phelan, K., Pina Aguilar, R. E., Poddighe, P. J., Pregno, G., Raskin, S., Reis, L., Rhead, W., Rita, D., Renkens, I., Roelens, F., Ruliera, J., Rump, P., Schilit, S. L., Shaheen, R., Sparkes, R., Spiegel, E., Stevens, B., Stone, M. R., Tagoe, J., Thakuria, J. V., van Bon, B. W., van de Kamp, J., van der Burgt, I., van Essen, T., van Ravenswaaij-Arts, C. M., van Roosmalen, M. J., Vergult, S., Volker-Touw, C. M., Warburton, D. P., Waterman, M. J., Wiley, S., Wilson, A., Yerena-de Vega, M. d., Zori, R. T., Levy, B., Brunner, H. G., de Leeuw, N., Kloosterman, W. P., Thorland, E. C., Morton, C. C., Gusella, J. F., Talkowski, M. E. 2017; 49 (1): 36-45

  Abstract

  Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. We propose that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements and provides insight into new pathogenic mechanisms, such as altered regulation due to changes in chromosome topology.

  View details for DOI 10.1038/ng.3720

  View details for Web of Science ID 000390976600009

• Impact of Huntington Disease Gene-Positive Status on Pre-Symptomatic Young Adults and Recommendations for Genetic Counselors JOURNAL OF GENETIC COUNSELING Gong, P., Fanos, J. H., Korty, L., Siskind, C. E., Hanson-Kahn, A. K. 2016; 25 (6): 1188-1197

  Abstract

  Huntington disease (HD) is an autosomal dominant, progressive neurodegenerative disorder for which there is no cure. Predictive testing for HD is available to asymptomatic at-risk individuals. Approximately half of the population undergoing predictive testing for HD consists of young adults (≤35 years old). Finishing one's education, starting a career, engaging in romantic relationships and becoming a parent are key milestones of young adulthood. We conducted a qualitative study to explore how testing gene-positive for HD influences young adults' attainment of these milestones, and to identify major challenges that pre-symptomatic young adults face to aid the development of targeted genetic counseling. Results of our study demonstrate that 1) knowing one's gene-positive status results in an urgency to reach milestones and positively changes young adults' approach to life; 2) testing positive influences young adults' education and career choices, romantic relationships, and family planning; 3) young adults desire flexible and tailored genetic counseling to address needs and concerns unique to this population. Findings of this study contribute to the understanding of the impact of predictive testing for HD on young adults, and highlight issues unique to this population that call for further research, intervention and advocacy.

  View details for DOI 10.1007/s10897-016-9951-z

  View details for Web of Science ID 000388177100006

  View details for PubMedID 27103420

• Clinical Course of Six Children With GNAO1 Mutations Causing a Severe and Distinctive Movement Disorder PEDIATRIC NEUROLOGY Ananth, A. L., Robichaux-Viehoever, A., Kim, Y., Hanson-Kahn, A., Cox, R., Enns, G. M., Strober, J., Willing, M., Schlaggar, B. L., Wu, Y. W., Bernstein, J. A. 2016; 59: 81-84

  Abstract

  Mutations in GNAO1 have been described in 11 patients to date. Although most of these individuals had epileptic encephalopathy, four patients had a severe movement disorder as the prominent feature. We describe the largest series of patients with de novoGNAO1 mutations who have severe chorea, developmental delay, and hypotonia in the absence of epilepsy.Six patients with recurrent missense mutations in GNAO1 as detected by whole exome sequencing were identified at three institutions. We describe the presentation, clinical course, and response to treatment of these patients.All six patients exhibited global developmental delay and hypotonia from infancy. Chorea developed by age four years in all but one patient, who developed chorea at 14 years. Treatments with neuroleptics and tetrabenazine were most effective in the baseline management of chorea. The chorea became gradually progressive and marked by episodes of severe, refractory ballismus requiring intensive care unit admissions in four of six patients. Exacerbations indirectly led to the death of two patients.Patients with GNAO1 mutations can present with a severe, progressive movement disorder in the absence of epilepsy. Exacerbations may be refractory to treatment and can result in life-threatening secondary complications. Early and aggressive treatment of these exacerbations with direct admission to intensive care units for treatment with anesthetic drips may prevent some secondary complications. However the chorea and ballismus can be refractory to maximum medical therapy.

  View details for DOI 10.1016/j.pediatrneurol.2016.02.018

  View details for PubMedID 27068059

• Clinical Delineation of the PACS1-Related Syndrome-Report on 19 Patients AMERICAN JOURNAL OF MEDICAL GENETICS PART A Schuurs-Hoeijmakers, J. H., Landsverk, M. L., Foulds, N., Kukolich, M. K., Gavrilova, R. H., Greville-Heygate, S., Hanson-Kahn, A., Bernstein, J. A., Glass, J., Chitayat, D., Burrow, T. A., Husami, A., Collins, K., Wusik, K., Van der Aa, N., Kooy, F., Brown, K. T., Gadzicki, D., Kini, U., Alvarez, S., Fernandez-Jaen, A., McGehee, F., Selby, K., Tarailo-Graovac, M., Van Allen, M., van Karnebeek, C. D., Stavropoulos, D. J., Marshall, C. R., Merico, D., Gregor, A., Zweier, C., Hopkin, R. J., Chu, Y. W., Chung, B. H., de Vries, B. B., Devriendt, K., Hurles, M. E., Brunner, H. G. 2016; 170 (3): 670-675

  Abstract

  We report on 19 individuals with a recurrent de novo c.607C>T mutation in PACS1. This specific mutation gives rise to a recognizable intellectual disability syndrome. There is a distinctive facial appearance (19/19), characterized by full and arched eyebrows, hypertelorism with downslanting palpebral fissures, long eye lashes, ptosis, low set and simple ears, bulbous nasal tip, wide mouth with downturned corners and a thin upper lip with an unusual "wavy" profile, flat philtrum, and diastema of the teeth. Intellectual disability, ranging from mild to moderate, was present in all. Hypotonia is common in infancy (8/19). Seizures are frequent (12/19) and respond well to anticonvulsive medication. Structural malformations are common, including heart (10/19), brain (12/16), eye (10/19), kidney (3/19), and cryptorchidism (6/12 males). Feeding dysfunction is presenting in infancy with failure to thrive (5/19), gastroesophageal reflux (6/19), and gastrostomy tube placement (4/19). There is persistence of oral motor dysfunction. We provide suggestions for clinical work-up and management and hope that the present study will facilitate clinical recognition of further cases. © 2016 Wiley Periodicals, Inc.

  View details for DOI 10.1002/ajmg.a.37476

  View details for PubMedID 26842493

• Cold-aggravated pain in humans caused by a hyperactive Na(V)1.9 channel mutant NATURE COMMUNICATIONS Leipold, E., Hanson-Kahn, A., Frick, M., Gong, P., Bernstein, J. A., Voigt, M., Katona, I., Goral, R. O., Altmueller, J., Nuernberg, P., Weis, J., Huebner, C. A., Heinemann, S. H., Kurth, I. 2015; 6

  Abstract

  Gain-of-function mutations in the human SCN11A-encoded voltage-gated Na(+) channel NaV1.9 cause severe pain disorders ranging from neuropathic pain to congenital pain insensitivity. However, the entire spectrum of the NaV1.9 diseases has yet to be defined. Applying whole-exome sequencing we here identify a missense change (p.V1184A) in NaV1.9, which leads to cold-aggravated peripheral pain in humans. Electrophysiological analysis reveals that p.V1184A shifts the voltage dependence of channel opening to hyperpolarized potentials thereby conferring gain-of-function characteristics to NaV1.9. Mutated channels diminish the resting membrane potential of mouse primary sensory neurons and cause cold-resistant hyperexcitability of nociceptors, suggesting a mechanistic basis for the temperature dependence of the pain phenotype. On the basis of direct comparison of the mutations linked to either cold-aggravated pain or pain insensitivity, we propose a model in which the physiological consequence of a mutation, that is, augmented versus absent pain, is critically dependent on the type of NaV1.9 hyperactivity.

  View details for DOI 10.1038/ncomms10049

  View details for Web of Science ID 000367568200002

• Cold-aggravated pain in humans caused by a hyperactive NaV1.9 channel mutant. Nature communications Leipold, E., Hanson-Kahn, A., Frick, M., Gong, P., Bernstein, J. A., Voigt, M., Katona, I., Oliver Goral, R., Altmüller, J., Nürnberg, P., Weis, J., Hübner, C. A., Heinemann, S. H., Kurth, I. 2015; 6: 10049-?

  Abstract

  Gain-of-function mutations in the human SCN11A-encoded voltage-gated Na(+) channel NaV1.9 cause severe pain disorders ranging from neuropathic pain to congenital pain insensitivity. However, the entire spectrum of the NaV1.9 diseases has yet to be defined. Applying whole-exome sequencing we here identify a missense change (p.V1184A) in NaV1.9, which leads to cold-aggravated peripheral pain in humans. Electrophysiological analysis reveals that p.V1184A shifts the voltage dependence of channel opening to hyperpolarized potentials thereby conferring gain-of-function characteristics to NaV1.9. Mutated channels diminish the resting membrane potential of mouse primary sensory neurons and cause cold-resistant hyperexcitability of nociceptors, suggesting a mechanistic basis for the temperature dependence of the pain phenotype. On the basis of direct comparison of the mutations linked to either cold-aggravated pain or pain insensitivity, we propose a model in which the physiological consequence of a mutation, that is, augmented versus absent pain, is critically dependent on the type of NaV1.9 hyperactivity.

  View details for DOI 10.1038/ncomms10049

  View details for PubMedID 26645915

• Underutilization of Genetics Services for Autism: The Importance of Parental Awareness and Provider Recommendation JOURNAL OF GENETIC COUNSELING Vande Wydeven, K., Kwan, A., Hardan, A. Y., Bernstein, J. A. 2012; 21 (6): 803-813

  Abstract

  Reasons for the underutilization of genetics services by families of children with autism spectrum disorders (ASD) are not well understood. We report the identification of factors associated with this underuse. Survey-based study of parents and/or guardians of children with ASD. One hundred fifty-five families completed the questionnaire. Thirty-one of 155 (20%) children had seen a genetics professional. Forty-nine of 154 (32%) children had undergone genetic testing. Parents whose child saw a genetics professional were more likely to 1) Have a primary provider refer for or suggest a genetics evaluation 2) Have asked for a referral, and/or 3) Know another person with a genetic cause of ASD. amilies of children with ASD who have not received genetics services are less aware of their availability and utility. They are also less likely to have their provider recommend a clinical genetics evaluation. Efforts should be taken to increase awareness of both health providers and parents regarding the usefulness of genetics services for ASD.

  View details for DOI 10.1007/s10897-012-9494-x

  View details for PubMedID 22415587

• Marked variability in the radiographic features of cartilage-hair hypoplasia: Case report and review of the literature AMERICAN JOURNAL OF MEDICAL GENETICS PART A Kwan, A., Manning, M. A., Zollars, L. K., Hoyme, H. E. 2012; 158A (11): 2911-2916

  Abstract

  Cartilage-hair hypoplasia (CHH) is a rare recessive metaphyseal chondrodysplasia characterized by severe short stature, ectodermal dysplasia, anemia in childhood, immune deficiency, susceptibility to malignancy, and normal intelligence. Short, thick long bones, metaphyseal flaring and irregularities, and globular epiphyses at the knees and ankles are the typical radiographic findings. The diagnosis is primarily made on the basis of clinical features, although mutations in the RMRP gene have recently been described in affected individuals, facilitating confirmation of the clinical diagnosis in atypical patients. We present a patient with two RMRP mutations whose stature and ectodermal features supported the diagnosis of CHH, but whose radiographic findings and other extraskeletal findings did not. We propose that the most consistent and reliable features of CHH are short stature of prenatal onset and ectodermal dysplasia, and suggest that the diagnosis of CHH be considered and mutation analysis pursued even when typical radiographic findings are absent.

  View details for DOI 10.1002/ajmg.a.35604

  View details for Web of Science ID 000310071700041

  View details for PubMedID 22987807

• Report of Two Patients and Further Characterization of Interstitial 9p13 Deletion-A Rare But Recurrent Microdeletion Syndrome? AMERICAN JOURNAL OF MEDICAL GENETICS PART A Niemi, A., Kwan, A., Hudgins, L., Cherry, A. M., Manning, M. 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

• What Is Your Diagnosis? The Diagnosis: Trichorhinophalangeal Syndrome Type I CUTIS Snyder, J. R., Berk, D. R., Kwan, A., Hudgins, L., Bruckner, A. L. 2012; 89 (2): 56-?

  View details for Web of Science ID 000300545400002

  View details for PubMedID 22474724

• Ectopia Lentis as the Presenting and Primary Feature in Marfan Syndrome AMERICAN JOURNAL OF MEDICAL GENETICS PART A Zadeh, N., Bernstein, J. A., Niemi, A. K., Dugan, S., Kwan, A., Liang, D., Hyland, J. C., Hoyme, H. E., Hudgins, L., Manning, M. 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

• Clues to an Early Diagnosis of Kallmann Syndrome AMERICAN JOURNAL OF MEDICAL GENETICS PART A Kaplan, J. D., Bernstein, J. A., Kwan, A., Hudgins, L. 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

• Brachydactyly A-1 mutations restricted to the central region of the N-terminal active fragment of Indian Hedgehog EUROPEAN JOURNAL OF HUMAN GENETICS Byrnes, A. M., Racacho, L., Grimsey, A., Hudgins, L., Kwan, A. C., Sangalli, M., Kidd, A., Yaron, Y., Lau, Y., Nikkel, S. M., Bulman, D. E. 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

• Hypoplastic Glomerulocystic Kidney Disease and Hepatoblastoma A Potential Association not Caused by Mutations in Hepatocyte Nuclear Factor 1 beta JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY Abdul-Rahman, O. A., Edghill, E. L., Kwan, A., Enns, G. M., Hattersley, A. T. 2009; 31 (7): 527-529

  Abstract

  Hypoplastic glomerulocystic kidney disease is an autosomal dominant disorder caused by mutations in hepatocyte nuclear factor-1beta. Hepatoblastoma is a sporadic occurring tumor of embryonal origin that has been associated with the several overgrowth syndromes. We report a case of concomitant hypoplastic glomerulocystic kidney disease and hepatoblastoma. Review of the literature identified 4 other patients with a similar association. We propose that hypoplastic glomerulocystic kidney disease and hepatoblastoma represent a possible association, and we excluded mutations in hepatocyte nuclear factor-1beta in our patient as causative of this putative association.

  View details for Web of Science ID 000267567800014

  View details for PubMedID 19564751

• Clinical Utility of Array Comparative Genomic Hybridization: Uncovering Tumor Susceptibility in Individuals with Developmental Delay JOURNAL OF PEDIATRICS Adam, M. P., Justice, A. N., Schelley, S., Kwan, A., Hudgins, L., Martin, C. L. 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

• Unilateral aquagenic wrinkling of the palms associated with aspirin intake ARCHIVES OF DERMATOLOGY Khuu, P. T., Duncan, K. O., Kwan, A., Hoyme, H. E., Bruckner, A. L. 2006; 142 (12): 1661-1662

  View details for Web of Science ID 000242803400033

  View details for PubMedID 17179009

• Genitopatellar syndrome: expanding the phenotype and excluding mutations in LMX1B and TBX4. American journal of medical genetics. Part A Abdul-Rahman, O. A., La, T. H., Kwan, A., Schlaubitz, S., Barsh, G. S., Enns, G. M., Hudgins, L. 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

• Methotrexate/misoprostol embryopathy: Report of four cases resulting from failed medical abortion Bryan D Hall Festschrift 2003 Adam, M. P., Manning, M. A., Beck, A. E., Kwan, A., Enns, G. M., Clericuzio, C., Hoyme, H. E. WILEY-LISS. 2003: 72–78

  Abstract

  Methotrexate, a methyl derivative of aminopterin, is a folic acid antagonist and a known human teratogen; misoprostol is a synthetic prostaglandin E1 analog that causes uterine contractions. Recently, there has been resurgence in the use of methotrexate in combination with misoprostol or of methotrexate alone for the treatment of unwanted or ectopic pregnancies, respectively. This report documents the findings in four infants who were exposed prenatally to methotrexate alone or in combination with misoprostol in a failed attempt at medical abortion or treatment of ectopic pregnancy. All patients demonstrated growth deficiency, with growth parameters <10th centile, and all displayed features consistent with methotrexate and/or misoprostol embryopathy. Since an increasing number of medical abortions are being performed, it is important for physicians to recognize the associated teratogenic effects of these abortifacients. Data from the patients herein described should prompt obstetricians and other health care practitioners who prescribe these medications to counsel their patients regarding these risks, especially if the treatment regimen fails to induce an abortion.

  View details for DOI 10.1002/ajmg.a.20503

  View details for PubMedID 14556250

• Sequence and analysis of chromosome 1 of the plant Arabidopsis thaliana NATURE Theologis, A., Ecker, J. R., Palm, C. J., Federspiel, N. A., Kaul, S., White, O., Alonso, J., Altafi, H., Araujo, R., Bowman, C. L., Brooks, S. Y., Buehler, E., Chan, A., Chao, Q. M., Chen, H. M., Cheuk, R. F., Chin, C. W., Chung, M. K., Conn, L., Conway, A. B., Conway, A. R., Creasy, T. H., Dewar, K., Dunn, P., Etgu, P., Feldblyum, T. V., Feng, J. D., Fong, B., Fujii, C. Y., Gill, J. E., Goldsmith, A. D., Haas, B., Hansen, N. F., Hughes, B., Huizar, L., Hunter, J. L., Jenkins, J., Johnson-Hopson, C., Khan, S., Khaykin, E., Kim, C. J., Koo, H. L., Kremenetskaia, I., Kurtz, D. B., Kwan, A., Lam, B., Langin-Hooper, S., Lee, A., Lee, J. M., Lenz, C. A., Li, J. H., Li, Y. P., Lin, X. Y., Liu, S. X., Liu, Z. A., Luros, J. S., Maiti, R., Marziali, A., Militscher, J., MIRANDA, M., Nguyen, M., Nierman, W. C., Osborne, B. I., Pai, G., Peterson, J., Pham, P. K., Rizzo, M., Rooney, T., Rowley, D., Sakano, H., Salzberg, S. L., Schwartz, J. R., Shinn, P., Southwick, A. M., Sun, H., Tallon, L. J., Tambunga, G., Toriumi, M. J., Town, C. D., Utterback, T., Van Aken, S., Vaysberg, M., Vysotskaia, V. S., Walker, M., Wu, D. Y., Yu, G. X., Fraser, C. M., Venter, J. C., Davis, R. W. 2000; 408 (6814): 816-820

  Abstract

  The genome of the flowering plant Arabidopsis thaliana has five chromosomes. Here we report the sequence of the largest, chromosome 1, in two contigs of around 14.2 and 14.6 megabases. The contigs extend from the telomeres to the centromeric borders, regions rich in transposons, retrotransposons and repetitive elements such as the 180-base-pair repeat. The chromosome represents 25% of the genome and contains about 6,850 open reading frames, 236 transfer RNAs (tRNAs) and 12 small nuclear RNAs. There are two clusters of tRNA genes at different places on the chromosome. One consists of 27 tRNA(Pro) genes and the other contains 27 tandem repeats of tRNA(Tyr)-tRNA(Tyr)-tRNA(Ser) genes. Chromosome 1 contains about 300 gene families with clustered duplications. There are also many repeat elements, representing 8% of the sequence.

  View details for Web of Science ID 000165831300038

  View details for PubMedID 11130712