Faculty Collaboration Database

Impact of MYH6 variants in hypoplastic left heart syndrome. Physiol Genomics 2016 Dec 01;48(12):912-921

Date

10/30/2016

Pubmed ID

27789736

Pubmed Central ID

PMC5206387

DOI

10.1152/physiolgenomics.00091.2016

Scopus ID

2-s2.0-85006309110 (requires institutional sign-in at Scopus site)   57 Citations

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 revealed differential expression of cardiac contractility genes, notably upregulation of the β-myosin heavy chain (MYH7) gene in subjects with MYH6 variants (P < 1 × 10^-3). We subsequently used patient-specific induced pluripotent stem cells (iPSCs) to model HLHS in vitro. Early stages of in vitro cardiomyogenesis in iPSCs derived from two unrelated HLHS families mimicked the increased expression of MYH7 observed in vivo (P < 1 × 10^-2), while revealing defective cardiomyogenic differentiation. Rare, damaging variants in MYH6 are enriched in HLHS, affect molecular expression of contractility genes, and are predictive of poor outcome. These findings indicate that the etiology of MYH6-associated HLHS can be informed using iPSCs and suggest utility in future clinical applications.

Author List

Tomita-Mitchell A, Stamm KD, Mahnke DK, Kim MS, Hidestrand PM, Liang HL, Goetsch MA, Hidestrand M, Simpson P, Pelech AN, Tweddell JS, Benson DW, Lough JW, Mitchell ME

Authors

John W. Lough PhD Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin
Donna K. Mahnke Research Scientist I in the Pediatrics department at Medical College of Wisconsin
Aoy Tomita Mitchell PhD Professor in the Surgery department at Medical College of Wisconsin
Michael Edward Mitchell MD Chief, Professor in the Surgery department at Medical College of Wisconsin
Pippa M. Simpson PhD Adjunct Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adolescent
Cardiac Myosins
Case-Control Studies
Cell Differentiation
Female
Humans
Hypoplastic Left Heart Syndrome
Induced Pluripotent Stem Cells
Male
Mutation
Myocytes, Cardiac
Myosin Heavy Chains
Pedigree
Transcriptome
Up-Regulation