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 #
3U54HG006504-03S1
Application #
8917008
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
2013-12-01
Budget End
2014-11-30
Support Year
3
Fiscal Year
2014
Total Cost
$75,000
Indirect Cost
Name
Yale University
Department
Genetics
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Besse, Whitney; Mansour, Sherry; Jatwani, Karan et al. (2016) Collapsing glomerulopathy in a young woman with APOL1 risk alleles following acute parvovirus B19 infection: a case report investigation. BMC Nephrol 17:125
Braun, Daniela A; Schueler, Markus; Halbritter, Jan et al. (2016) Whole exome sequencing identifies causative mutations in the majority of consanguineous or familial cases with childhood-onset increased renal echogenicity. Kidney Int 89:468-75
Li, Na; Subrahmanyan, Lakshman; Smith, Emily et al. (2016) Mutations in the Histone Modifier PRDM6 Are Associated with Isolated Nonsyndromic Patent Ductus Arteriosus. Am J Hum Genet 98:1082-91
Levinsohn, Jonathan L; Sugarman, Jeffrey L; Yale Center for Mendelian Genomics et al. (2016) Somatic Mutations in NEK9 Cause Nevus Comedonicus. Am J Hum Genet 98:1030-7
Madeo, Marianna; Stewart, Michelle; Sun, Yuyang et al. (2016) Loss-of-Function Mutations in FRRS1L Lead to an Epileptic-Dyskinetic Encephalopathy. Am J Hum Genet 98:1249-55
Johansen, Anide; Rosti, Rasim O; Musaev, Damir et al. (2016) Mutations in MBOAT7, Encoding Lysophosphatidylinositol Acyltransferase I, Lead to Intellectual Disability Accompanied by Epilepsy and Autistic Features. Am J Hum Genet 99:912-916
Boyden, Lynn M; Kam, Chen Y; Hernández-Martín, Angela et al. (2016) Dominant de novo DSP mutations cause erythrokeratodermia-cardiomyopathy syndrome. Hum Mol Genet 25:348-57
Scott, Eric M; Halees, Anason; Itan, Yuval et al. (2016) Characterization of Greater Middle Eastern genetic variation for enhanced disease gene discovery. Nat Genet 48:1071-6
Jerber, Julie; Zaki, Maha S; Al-Aama, Jumana Y et al. (2016) Biallelic Mutations in TMTC3, Encoding a Transmembrane and TPR-Containing Protein, Lead to Cobblestone Lissencephaly. Am J Hum Genet 99:1181-1189
Çağlayan, Ahmet O; Tüysüz, Beyhan; Coşkun, Süleyman et al. (2016) A patient with a novel homozygous missense mutation in FTO and concomitant nonsense mutation in CETP. J Hum Genet 61:395-403

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