The identification of mutations causing Mendelian diseases has revolutionized the understanding of diseases of every organ system. While over 3,000 such diseases have been solved at the molecular level, with 21,000 genes in the human genome and about 15% embryonic lethal loci, it is clear that many remain to be discovered. This includes both described and presently undescribed human traits that contribute to both health and disease. With the spectacular 6-log drop in the cost of DNA sequencing over the last 12 years, it has become apparent that selectively sequencing all of the genes in the genome, which comprise only ~1 % of the human genome represents a very cost-effective means for discovering the basis of new Mendelian diseases. We have pioneered the development of the exome sequencing method as well as the tools for analysis, and have shown that both are scalable, with current cost under $1,500 per exome and expected to be under $1,000 in the near future. We have demonstrated the utility of this approach with the identification of a range of disease genes that were previously intractable due to difficulties in gene mapping owing to high locus heterogeneity, de novo mutations, or small one-of-a-kind families. These considerations motivate new efforts to efficiently solve substantially all Mendelian traits using these technologies. To this end we have established the Yale Center for Mendelian Disorders which will ascertain and acquire samples from patients and families with known or suspected Mendelian diseases, sequence exomes to high coverage sufficient to call 95% of all variants with high specificity and use new analytic approaches we have devised to identify new Mendelian trait genes. We will make all sequences available to the research community as allowed and will establish a Web interface to enable physicians and investigators to submit research samples and retrieve annotated results. These studies will rapidly expand our understanding of the genes and pathways underlying human disease.

Public Health Relevance

Sequencing all of the genes in the genome is a new method for discovering gene mutations that cause specific human diseases. The discovery of the inherited basis for those diseases that are caused by a single mutation provides a foundation for the understanding of human health and disease and identifies specific biochemical pathways that might be altered for health benefit, as well as new tools for early diagnosis.

Agency
National Institute of Health (NIH)
Institute
National Human Genome Research Institute (NHGRI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54HG006504-02
Application #
8393218
Study Section
Special Emphasis Panel (ZHG1-HGR-P (O2))
Program Officer
Wang, Lu
Project Start
2011-12-05
Project End
2015-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
2
Fiscal Year
2013
Total Cost
$2,643,825
Indirect Cost
$1,180,435
Name
Yale University
Department
Genetics
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Sanna-Cherchi, Simone; Khan, Kamal; Westland, Rik et al. (2017) Exome-wide Association Study Identifies GREB1L Mutations in Congenital Kidney Malformations. Am J Hum Genet 101:789-802
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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
Marin-Valencia, Isaac; Gerondopoulos, Andreas; Zaki, Maha S et al. (2017) Homozygous Mutations in TBC1D23 Lead to a Non-degenerative Form of Pontocerebellar Hypoplasia. Am J Hum Genet 101:441-450
Boyden, L M; Craiglow, B G; Hu, R H et al. (2017) Phenotypic spectrum of autosomal recessive congenital ichthyosis due to PNPLA1 mutation. Br J Dermatol 177:319-322
Friedman, Jennifer; Feigenbaum, Annette; Chuang, Nathaniel et al. (2017) Pyruvate dehydrogenase complex-E2 deficiency causes paroxysmal exercise-induced dyskinesia. Neurology 89:2297-2298
Vivante, Asaf; Mann, Nina; Yonath, Hagith et al. (2017) A Dominant Mutation in Nuclear Receptor Interacting Protein 1 Causes Urinary Tract Malformations via Dysregulation of Retinoic Acid Signaling. J Am Soc Nephrol 28:2364-2376
Boyden, Lynn M; Vincent, Nicholas G; Zhou, Jing et al. (2017) Mutations in KDSR Cause Recessive Progressive Symmetric Erythrokeratoderma. Am J Hum Genet 100:978-984
Jin, Sheng Chih; Homsy, Jason; Zaidi, Samir et al. (2017) Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands. Nat Genet 49:1593-1601
Agopian, A J; Goldmuntz, Elizabeth; Hakonarson, Hakon et al. (2017) Genome-Wide Association Studies and Meta-Analyses for Congenital Heart Defects. Circ Cardiovasc Genet 10:e001449

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