The biomedical value of identifying the genes and variants responsible for Mendelian disorders is extraordinarily high. The clinical manifestations of these disorders involve developmental and physiological parameters of virtually all organ systems. About a third of recognized Mendelian disorders (as enumerated in the OMIM database) remain unexplained at the molecular level and many more of these disorders remain to be recognized, described and explained. Over the last eight years, the Baylor College of Medicine and Johns Hopkins University School of Medicine human genetics programs have combined and formed the Baylor-Hopkins Center for Mendelian Genomics (BHCMG) to address this problem. In doing so, we have taken advantage of the synergies afforded by combining our expertise in clinical genetics, genomic technologies, genetic analysis and understanding the biological basis of genetic disease. We have met and will continue to meet the challenge of finding and recruiting for our research patients with unexplained Mendelian disorders and by utilizing our worldwide network of colleagues and former trainees. Using state of the art genomic methods and analytic tools, we have already sequenced the exome or the genome of 10,827 individuals, identifying 358 novel disease genes, and have another > 5,000 samples ready to sequence from collaborators in the USA and 40 other countries. This effort has resulted in 273 peer- reviewed papers from BHCMG. In the future, we will expand this network of collaborators to identify more samples. To assist in consenting samples from around the world, we have designed an online consenting process approved by our IRB that bypasses the bottlenecks of time difference and language in international and remote site recruiting. To streamline and monitor our progress we continue to enhance PhenoDB, a web-based tool for the collection, storage and analysis of phenotypic features and genotype information. PhenoDB also tracks samples, and is updated with the deliberations of our expert committees for Phenotype Review and ELSI issues. PhenoDB is fully searchable and incorporates OMIM for disease classification and genes, as well as many other resources to enable analysis. We have and will continue to build on our existing high throughput sequencing pipelines and have developed integrated laboratory and analysis efforts with experts from both institutions to develop new methods and software to advance the field. To promote data sharing, we are aggregating exome sequencing data and phenotypic data produced at BCM and at JH in a data lake suitable for joint analysis. We have and will disseminate the phenotype and molecular information through publication, lectures, posting to communal websites and dbGaP. Our GeneMatcher online tool now has > 11,000 genes submitted by >7,000 investigators and cited in > 150 publications and is part of the MatchMaker Exchange initiative involving geneticists around the world. We have also recently added a VariantMatcher functionality to PhenoDB that is accessible to all investigators.

Public Health Relevance

The Baylor ? Hopkins Center for Mendelian Genomics or BHCMG, is a partnership between two distinguished programs in human genetics, to recruit patients with Mendelian disorders and identify the genetic variants responsible for their disorder. We use state of the art genetics and genomics technology and analyses to meet this challenge. Our results provide the knowledge necessary for diagnosis and development of rational treatments for these disorders.

Agency
National Institute of Health (NIH)
Institute
National Human Genome Research Institute (NHGRI)
Type
Research Project with Complex Structure Cooperative Agreement (UM1)
Project #
3UM1HG006542-08S1
Application #
9923273
Study Section
Program Officer
Chadwick, Lisa
Project Start
2011-12-05
Project End
2020-11-30
Budget Start
2019-12-01
Budget End
2020-11-30
Support Year
8
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
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Wang, Kun; Zhao, Sen; Liu, Bowen et al. (2018) Perturbations of BMP/TGF-? and VEGF/VEGFR signalling pathways in non-syndromic sporadic brain arteriovenous malformations (BAVM). J Med Genet 55:675-684
Dinckan, Nuriye; Du, Renqian; Akdemir, Zeynep C et al. (2018) A biallelic ANTXR1 variant expands the anthrax toxin receptor associated phenotype to tooth agenesis. Am J Med Genet A 176:1015-1022
Punetha, Jaya; Mackay-Loder, Loren; Harel, Tamar et al. (2018) Identification of a pathogenic PMP2 variant in a multi-generational family with CMT type 1: Clinical gene panels versus genome-wide approaches to molecular diagnosis. Mol Genet Metab 125:302-304
Karaca, Ender; Posey, Jennifer E; Coban Akdemir, Zeynep et al. (2018) Phenotypic expansion illuminates multilocus pathogenic variation. Genet Med :
Jiang, Yunyun; Wangler, Michael F; McGuire, Amy L et al. (2018) The phenotypic spectrum of Xia-Gibbs syndrome. Am J Med Genet A 176:1315-1326
Cheng, Hanyin; Dharmadhikari, Avinash V; Varland, Sylvia et al. (2018) Truncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies. Am J Hum Genet 102:985-994
White, Janson J; Mazzeu, Juliana F; Coban-Akdemir, Zeynep et al. (2018) WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome. Am J Hum Genet 102:27-43
Poli, M Cecilia; Ebstein, Frédéric; Nicholas, Sarah K et al. (2018) Heterozygous Truncating Variants in POMP Escape Nonsense-Mediated Decay and Cause a Unique Immune Dysregulatory Syndrome. Am J Hum Genet 102:1126-1142
Wiszniewski, Wojciech; Gawlinski, Pawel; Gambin, Tomasz et al. (2018) Comprehensive genomic analysis of patients with disorders of cerebral cortical development. Eur J Hum Genet 26:1121-1131

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