Exome sequencing in multiplex families with left-sided cardiac defects has high yield for disease gene discovery |
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Authors: | David M. Gordon David Cunningham Gloria Zender Patrick J. Lawrence Jacqueline S. Penaloza Hui Lin Sara M. Fitzgerald-Butt Katherine Myers Tiffany Duong Donald J. Corsmeier Jeffrey B. Gaither Harkness C. Kuck Saranga Wijeratne Blythe Moreland Benjamin J. Kelly Baylor-Johns Hopkins Center for Mendelian Genomics Vidu Garg Peter White Kim L. McBride |
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Affiliation: | 1. Computational Genomics Group, The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, Ohio, United States of America;2. Center for Cardiovascular Research and The Heart Center, Nationwide Children’s Hospital, Columbus, Ohio, United States of America;3. Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, Ohio, United States of America; Broad Institute, UNITED STATES |
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Abstract: | Congenital heart disease (CHD) is a common group of birth defects with a strong genetic contribution to their etiology, but historically the diagnostic yield from exome studies of isolated CHD has been low. Pleiotropy, variable expressivity, and the difficulty of accurately phenotyping newborns contribute to this problem. We hypothesized that performing exome sequencing on selected individuals in families with multiple members affected by left-sided CHD, then filtering variants by population frequency, in silico predictive algorithms, and phenotypic annotations from publicly available databases would increase this yield and generate a list of candidate disease-causing variants that would show a high validation rate. In eight of the nineteen families in our study (42%), we established a well-known gene/phenotype link for a candidate variant or performed confirmation of a candidate variant’s effect on protein function, including variants in genes not previously described or firmly established as disease genes in the body of CHD literature: BMP10, CASZ1, ROCK1 and SMYD1. Two plausible variants in different genes were found to segregate in the same family in two instances suggesting oligogenic inheritance. These results highlight the need for functional validation and demonstrate that in the era of next-generation sequencing, multiplex families with isolated CHD can still bring high yield to the discovery of novel disease genes. |
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