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.
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.
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|Lopez-Rivera, Esther; Liu, Yangfan P; Verbitsky, Miguel et al. (2017) Genetic Drivers of Kidney Defects in the DiGeorge Syndrome. N Engl J Med 376:742-754|
|Besse, Whitney; Dong, Ke; Choi, Jungmin et al. (2017) Isolated polycystic liver disease genes define effectors of polycystin-1 function. J Clin Invest 127:1772-1785|
|Lovric, Svjetlana; Goncalves, Sara; Gee, Heon Yung et al. (2017) Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency. J Clin Invest 127:912-928|
|Timberlake, Andrew T; Furey, Charuta G; Choi, Jungmin et al. (2017) De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis. Proc Natl Acad Sci U S A 114:E7341-E7347|
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|Toriyama, Michinori; Lee, Chanjae; Taylor, S Paige et al. (2016) The ciliopathy-associated CPLANE proteins direct basal body recruitment of intraflagellar transport machinery. Nat Genet 48:648-56|
|Clarke, Declan; Sethi, Anurag; Li, Shantao et al. (2016) Identifying Allosteric Hotspots with Dynamics: Application to Inter- and Intra-species Conservation. Structure 24:826-837|
|Braun, Daniela A; Sadowski, Carolin E; Kohl, Stefan et al. (2016) Mutations in nuclear pore genes NUP93, NUP205 and XPO5 cause steroid-resistant nephrotic syndrome. Nat Genet 48:457-65|
|Priest, James R; Osoegawa, Kazutoyo; Mohammed, Nebil et al. (2016) De Novo and Rare Variants at Multiple Loci Support the Oligogenic Origins of Atrioventricular Septal Heart Defects. PLoS Genet 12:e1005963|
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