This is a renewal application for the Yale Center for Mendelian Genomics. The biology linking Mendelian mutations to traits has transformed our understanding of every organ system, identifying therapeutic targets, and allowing preclinical diagnosis and mitigation of disease risk. We know the consequence of mutation of fewer than 3,000 genes. With ~19,000 protein-coding genes, the vast majority of which are conserved across phylogeny, even allowing for 30% lethality, there are doubtless thousands of Mendelian loci awaiting discovery. The full utility of clinical sequencing will not be realized without bette understanding of the consequence of mutation of every gene. The advent of robust exome and genome sequencing allows unprecedented opportunity for discovery of new Mendelian trait loci. In the current cycle, by sequencing more than 7000 exomes from investigators world-wide we have identified 180 new Mendelian trait loci with high confidence, 35 phenotypic expansions, and hundreds more that are likely new trait loci across a range of traits and genetic mechanisms, including de novo mutations, incomplete penetrance, and complex rare recessive traits. Several new loci have immediate therapeutic implications. These results underscore that many new trait loci remain to be described and solved, motivating efforts to complete the human `knock out' map. We now propose, by building upon the current studies and through reduction in high quality exome cost to $330, to identify at least another 500 trait loci via the sequencing of more than 20,000 samples, advancing the understanding of genomes, health and disease.

Public Health Relevance

The vast majority of genomic variation in Mendelian disorders is due to variation in protein coding regions in the genome. Capture and sequencing of these regions allow for rapid identification of disease causing mutations, which will allow us t understand and dissect the biology of these disorders leading to better diagnostic and therapeutic tools. At Yale Center for Mendelian Genomics, we have already collected over 5,000 such samples and now propose to sequence these samples and additional ones available from other institutions using next generation technologies and share this data with the general scientific community.

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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Wellington, Christopher
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Yale University
Schools of Medicine
New Haven
United States
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Scholl, Ute I; Stölting, Gabriel; Schewe, Julia et al. (2018) CLCN2 chloride channel mutations in familial hyperaldosteronism type II. Nat Genet 50:349-354
Yilmaz, Saliha; Uluda? Alkaya, Dilek; Kasapçopur, Özgür et al. (2018) Genotype-phenotype investigation of 35 patients from 11 unrelated families with camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome. Mol Genet Genomic Med 6:230-248
Winawer, Melodie R; Griffin, Nicole G; Samanamud, Jorge et al. (2018) Somatic SLC35A2 variants in the brain are associated with intractable neocortical epilepsy. Ann Neurol 83:1133-1146
van der Ven, Amelie T; Kobbe, Birgit; Kohl, Stefan et al. (2018) A homozygous missense variant in VWA2, encoding an interactor of the Fraser-complex, in a patient with vesicoureteral reflux. PLoS One 13:e0191224
Breuss, Martin W; Nguyen, An; Song, Qiong et al. (2018) Mutations in LNPK, Encoding the Endoplasmic Reticulum Junction Stabilizer Lunapark, Cause a Recessive Neurodevelopmental Syndrome. Am J Hum Genet 103:296-304
Craiglow, Brittany G; Boyden, Lynn M; Hu, Ronghua et al. (2018) CARD14-associated papulosquamous eruption: A spectrum including features of psoriasis and pityriasis rubra pilaris. J Am Acad Dermatol 79:487-494
Wang, Sheng; Mandell, Jeffrey D; Kumar, Yogesh et al. (2018) De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis. Cell Rep 24:3441-3454.e12
Warejko, Jillian K; Schueler, Markus; Vivante, Asaf et al. (2018) Whole Exome Sequencing Reveals a Monogenic Cause of Disease in ?43% of 35 Families With Midaortic Syndrome. Hypertension 71:691-699
Braun, Daniela A; Warejko, Jillian K; Ashraf, Shazia et al. (2018) Genetic variants in the LAMA5 gene in pediatric nephrotic syndrome. Nephrol Dial Transplant :
Warejko, Jillian K; Tan, Weizhen; Daga, Ankana et al. (2018) Whole Exome Sequencing of Patients with Steroid-Resistant Nephrotic Syndrome. Clin J Am Soc Nephrol 13:53-62

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