Impact of MYH6 Variants in Hypoplastic Left Heart Syndrome

Published on Dec 1, 2016in Physiological Genomics2.749
· DOI :10.1152/PHYSIOLGENOMICS.00091.2016
Aoy Tomita-Mitchell19
Estimated H-index: 19
(MCW: Medical College of Wisconsin),
Karl Stamm8
Estimated H-index: 8
(Marquette University)
+ 11 AuthorsMichael E. Mitchell17
Estimated H-index: 17
(MCW: Medical College of Wisconsin)
Sources
Abstract
Hypoplastic left heart syndrome (HLHS) is a clinically and anatomically severe form of congenital heart disease (CHD). Although prior studies suggest that HLHS has a complex genetic inheritance, its etiology remains largely unknown. The goal of this study was to characterize a risk gene in HLHS and its effect on HLHS etiology and outcome. We performed next-generation sequencing on a multigenerational family with a high prevalence of CHD/HLHS, identifying a rare variant in the α-myosin heavy chain (MYH6) gene. A case-control study of 190 unrelated HLHS subjects was then performed and compared with the 1000 Genomes Project. Damaging MYH6 variants, including novel, missense, in-frame deletion, premature stop, de novo, and compound heterozygous variants, were significantly enriched in HLHS cases (P < 1 × 10−5). Clinical outcomes analysis showed reduced transplant-free survival in HLHS subjects with damaging MYH6 variants (P < 1 × 10−2). Transcriptome and protein expression analyses with cardiac tissue reveale...
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