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.
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.
| Dobyns, William B; Aldinger, Kimberly A; Ishak, Gisele E et al. (2018) MACF1 Mutations Encoding Highly Conserved Zinc-Binding Residues of the GAR Domain Cause Defects in Neuronal Migration and Axon Guidance. Am J Hum Genet 103:1009-1021 |
| Latif, Zahid; Chakchouk, Imen; Schrauwen, Isabelle et al. (2018) Confirmation of the Role of DHX38 in the Etiology of Early-Onset Retinitis Pigmentosa. Invest Ophthalmol Vis Sci 59:4552-4557 |
| Gregor, Anne; Sadleir, Lynette G; Asadollahi, Reza et al. (2018) De Novo Variants in the F-Box Protein FBXO11 in 20 Individuals with a Variable Neurodevelopmental Disorder. Am J Hum Genet 103:305-316 |
| Schrauwen, Isabelle; Chakchouk, Imen; Acharya, Anushree et al. (2018) Novel digenic inheritance of PCDH15 and USH1G underlies profound non-syndromic hearing impairment. BMC Med Genet 19:122 |
| Bamshad, Michael J; Magoulas, Pilar L; Dent, Karin M (2018) Genetic counselors on the frontline of precision health. Am J Med Genet C Semin Med Genet 178:5-9 |
| Moccia, Amanda; Srivastava, Anshika; Skidmore, Jennifer M et al. (2018) Genetic analysis of CHARGE syndrome identifies overlapping molecular biology. Genet Med 20:1022-1029 |
| Mori, Takayasu; Yousefzadeh, Matthew J; Faridounnia, Maryam et al. (2018) ERCC4 variants identified in a cohort of patients with segmental progeroid syndromes. Hum Mutat 39:255-265 |
| Schrauwen, Isabelle; Chakchouk, Imen; Liaqat, Khurram et al. (2018) A variant in LMX1A causes autosomal recessive severe-to-profound hearing impairment. Hum Genet 137:471-478 |
| Di Donato, Nataliya; Timms, Andrew E; Aldinger, Kimberly A et al. (2018) Analysis of 17 genes detects mutations in 81% of 811 patients with lissencephaly. Genet Med 20:1354-1364 |
| Guo, Dong-Chuan; Regalado, Ellen S; Pinard, Amelie et al. (2018) LTBP3 Pathogenic Variants Predispose Individuals to Thoracic Aortic Aneurysms and Dissections. Am J Hum Genet 102:706-712 |
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