To date, 2,937 genes underlying 4,163 Mendelian conditions (MCs) has been discovered. However, the genetic basis of over 3,000 MCs remains unknown, and hundreds of novel MCs are described each year. In 2011, the NHGRI and NHLBI established the Centers for Mendelian Genomics (CMG) to facilitate large-scale discovery of genes responsible for MCs. In Phase-1 of the CMG program, and in partnership with 182 investigators from 117 institutions in 27 countries, the University of Washington CMG (UW-CMG) assessed 6,598 samples from 2,404 families and has, to date, produced 4,116 exome and 97 whole genome sequences. This extensive collaborative effort resulted in an unparalleled pace of discovery with the identification of genes for 237 MCs, including 123 novel discoveries. The translation and impact of these discoveries on diagnostics and clinical care has been immediate and substantial-when combined with discoveries made by the genetics community at-large, variants in genes identified as underlying MCs since 2012 represent ~25% of positive results in clinical diagnostic efforts. Additionally, the UW-CMG has developed multiple new analytical tools including CADD, PRIMUS, SimRare, STAR, RV-TDT, CHP, VAT and Spliceosaurus as well as methodological innovations including MIPs, smMIPs and approaches for low input exome and genome sequencing. The UW-CMG remains deeply committed to open data sharing with rolling submission of eligible exome and genome data to dbGaP (614 deposited and 1,748 pending deposition) and development of a new data browser ( that, for the first time, publicly provides anonymized links between individual-level genotypes, from over 3,000 exomes, to individual clinical phenotypes, defined by Human Phenotype Ontology terms. In this renewal application, we build from these successes to maximize novel gene discovery for MCs, capitalizing on immediate access to >22,000 sequence-ready samples from >16,500 families and 163 MCs, access to several large cohorts of birth defects totaling more than 24,000 trios (>94,000 samples total) and an aggressive sample solicitation plan including case aggregation and case matching of undiagnosed patients who have undergone clinical exome sequencing. We propose four specific aims: (1) Solicit, organize, and curate phenotypic information and DNA samples from families with unexplained (i.e., no known underlying gene) MCs from sample custodians around the world, by submission to our center of either samples for sequencing or sequence data for further analysis; (2) Apply our established production pipeline for exome and genome sequencing to samples corresponding to unexplained MCs and to improve this process through ongoing technology innovation; (3) Determine the genetic basis of as many unexplained MCs as is possible, maximizing novel discovery, by use of efficient study design and effective, innovative analysis; (4) Take a leadership role to disseminate and openly share methods and data to promote worldwide efforts to discover the full complement of genes underlying MCs.

Public Health Relevance

Mendelian conditions, many of which are diseases but also include phenotypic differences that may not be considered a 'disease,' are caused mainly by mutations in the protein coding regions of the genome. Although the genes underlying thousands of Mendelian phenotypes have been identified, there are thousands of Mendelian conditions for which the gene(s) remain to be discovered. We propose to use an extensive network of clinicians and investigators, next-generation sequencing coupled with new analytical paradigms and technological innovations to efficiently discover novel genes for as many Mendelian conditions as possible.

National Institute of Health (NIH)
National Human Genome Research Institute (NHGRI)
Research Project with Complex Structure Cooperative Agreement (UM1)
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Special Emphasis Panel (ZHG1)
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Wang, Lu
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University of Washington
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Shahzad, Mohsin; Yousaf, Sairah; Waryah, Yar M et al. (2017) Molecular outcomes, clinical consequences, and genetic diagnosis of Oculocutaneous Albinism in Pakistani population. Sci Rep 7:44185
Kim, Daniel Seung; Burt, Amber A; Ranchalis, Jane E et al. (2017) Sequencing of sporadic Attention-Deficit Hyperactivity Disorder (ADHD) identifies novel and potentially pathogenic de novo variants and excludes overlap with genes associated with autism spectrum disorder. Am J Med Genet B Neuropsychiatr Genet 174:381-389
Guo, Dong-Chuan; Duan, Xue-Yan; Regalado, Ellen S et al. (2017) Loss-of-Function Mutations in YY1AP1 Lead to Grange Syndrome and a Fibromuscular Dysplasia-Like Vascular Disease. Am J Hum Genet 100:21-30
Badiner, N; Taylor, S P; Forlenza, K et al. (2017) Mutations in DYNC2H1, the cytoplasmic dynein 2, heavy chain 1 motor protein gene, cause short-rib polydactyly type I, Saldino-Noonan type. Clin Genet 92:158-165
Ng, Bobby G; Asteggiano, Carla G; Kircher, Martin et al. (2017) Encephalopathy caused by novel mutations in the CMP-sialic acid transporter, SLC35A1. Am J Med Genet A 173:2906-2911
Milunsky, Aubrey; Baldwin, Clinton; Zhang, Xiaoying et al. (2017) Diagnosis of Chronic Intestinal Pseudo-obstruction and Megacystis by Sequencing the ACTG2 Gene. J Pediatr Gastroenterol Nutr 65:384-387
Keller, Rachel B; Tran, Thao T; Pyott, Shawna M et al. (2017) Monoallelic and biallelic CREB3L1 variant causes mild and severe osteogenesis imperfecta, respectively. Genet Med :
Maselli, Ricardo A; Arredondo, Juan; Vázquez, Jessica et al. (2017) Presynaptic congenital myasthenic syndrome with a homozygous sequence variant in LAMA5 combines myopia, facial tics, and failure of neuromuscular transmission. Am J Med Genet A 173:2240-2245
Tabor, Holly K; Jamal, Seema M; Yu, Joon-Ho et al. (2017) My46: a Web-based tool for self-guided management of genomic test results in research and clinical settings. Genet Med 19:467-475
Turner, Tychele N; Yi, Qian; Krumm, Niklas et al. (2017) denovo-db: a compendium of human de novo variants. Nucleic Acids Res 45:D804-D811

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