Over the past three decades, the genes underlying nearly 3,000 Mendelian disorders have been identified by methods such as linkage analysis and positional cloning. Although the availability of a reference human genome greatly accelerated these efforts, there are thousands of additional suspected Mendelian disorders that remain unsolved. An understanding of the genetic basis of a Mendelian disorder can yield fundamental insights into basic human biology and disease pathophysiology, as well as a molecular basis for diagnosis or carrier status determination. In some instances, biological insights from studying Mendelian disorders can prove highly relevant to our understanding of more common diseases. Recently, we and others have shown that the coupling of targeted capture and next-generation DNA sequencing technology can be used to cost-effectively determine nearly all coding variation in an individual human genome, a process termed exome sequencing. We, and others, have also demonstrated how exome sequencing can be applied to efficiently identify the causal genes for Mendelian disorders that have proven intractable to conventional modes of analysis. To accelerate progress towards a comprehensive understanding of the genetic basis of all Mendelian disorders, we propose to establish the UW Center for Mendelian Genomics. Our proposal has four specific aims: (1) To organize samples for all unsolved Mendelian disorders from investigators around the world, either by their submission to our center for sequencing, or by their inclusion on a public sample list that we will develop;(2) To apply our existing production pipeline for exome and genome sequencing to samples corresponding to unsolved Mendelian disorders, and to improve this process through ongoing technology innovation;(3) To determine the genetic basis for as many unsolved Mendelian disorders as possible, through efficient study design and effective, innovative analysis;(4) To take a leadership role in the dissemination of methods and data.

Public Health Relevance

Mendelian disorders are rare diseases caused by mutations in single genes. Over the past three decades, the genes underlying thousands of Mendelian disorders have been identified. However, there are thousands of additional Mendelian disorders, the genetic basis for which has yet to be determined. We propose to apply new technologies and new analytical paradigms to efficiently determine the genetic basis of nearly all unsolved Mendelian disorders.

National Institute of Health (NIH)
National Human Genome Research Institute (NHGRI)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZHG1-HGR-P (O2))
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Wang, Lu
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University of Washington
Schools of Medicine
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Bennett, James T; Tan, Tiong Yang; Alcantara, Diana et al. (2016) Mosaic Activating Mutations in FGFR1 Cause Encephalocraniocutaneous Lipomatosis. Am J Hum Genet 98:579-87
Chen, Dong-Hui; Below, Jennifer E; Shimamura, Akiko et al. (2016) Ataxia-Pancytopenia Syndrome Is Caused by Missense Mutations in SAMD9L. Am J Hum Genet 98:1146-58
Ansar, Muhammad; Jan, Abid; Santos-Cortez, Regie Lyn P et al. (2016) Expansion of the spectrum of ITGB6-related disorders to adolescent alopecia, dentogingival abnormalities and intellectual disability. Eur J Hum Genet 24:1223-7
Wallace, S; Guo, D-C; Regalado, E et al. (2016) Disrupted nitric oxide signaling due to GUCY1A3 mutations increases risk for moyamoya disease, achalasia and hypertension. Clin Genet 90:351-60
Ullah, Rahim; Ansar, Muhammad; Durrani, Zaka Ullah et al. (2016) Novel mutations in the genes TGM1 and ALOXE3 underlying autosomal recessive congenital ichthyosis. Int J Dermatol 55:524-30
Staples, Jeffrey; Witherspoon, David J; Jorde, Lynn B et al. (2016) PADRE: Pedigree-Aware Distant-Relationship Estimation. Am J Hum Genet 99:154-62
Duran, Ivan; Taylor, S Paige; Zhang, Wenjuan et al. (2016) Destabilization of the IFT-B cilia core complex due to mutations in IFT81 causes a Spectrum of Short-Rib Polydactyly Syndrome. Sci Rep 6:34232
Guo, Dong-chuan; Regalado, Ellen S; Gong, Limin et al. (2016) LOX Mutations Predispose to Thoracic Aortic Aneurysms and Dissections. Circ Res 118:928-34
Kapferer-Seebacher, Ines; Pepin, Melanie; Werner, Roland et al. (2016) Periodontal Ehlers-Danlos Syndrome Is Caused by Mutations in C1R and C1S, which Encode Subcomponents C1r and C1s of Complement. Am J Hum Genet 99:1005-1014
Wang, Longfei; Lee, Sungyoung; Gim, Jungsoo et al. (2016) Family-Based Rare Variant Association Analysis: A Fast and Efficient Method of Multivariate Phenotype Association Analysis. Genet Epidemiol 40:502-11

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