title: Impact of MYH6 variants in hypoplastic left heart syndrome.
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.
authors: Department of Surgery, Division of Cardiovascular Surgery and Children's Research Institute, Medical College of Wisconsin, Milwaukee, Wisconsin; amitchell@mcw.edu.
authors: Aoy
authors: A
authors: Tomita-Mitchell
authors: Department of Surgery, Division of Cardiovascular Surgery and Children's Research Institute, Medical College of Wisconsin, Milwaukee, Wisconsin.|Department of Mathematics, Statistics and Computer Science, Marquette University, Milwaukee, Wisconsin.
authors: Karl D
authors: KD
authors: Stamm
authors: Department of Surgery, Division of Cardiovascular Surgery and Children's Research Institute, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors: Donna K
authors: DK
authors: Mahnke
authors: Department of Surgery, Division of Cardiovascular Surgery and Children's Research Institute, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors: Min-Su
authors: MS
authors: Kim
authors: Department of Pediatric Cardiology, Eastern Maine Medical Center, Bangor, Maine.
authors: Pip M
authors: PM
authors: Hidestrand
authors: Department of Surgery, Division of Cardiovascular Surgery and Children's Research Institute, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors: Huan Ling
authors: HL
authors: Liang
authors: Department of Surgery, Division of Cardiovascular Surgery and Children's Research Institute, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors: Mary A
authors: MA
authors: Goetsch
authors: Department of Surgery, Division of Cardiovascular Surgery and Children's Research Institute, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors: Mats
authors: M
authors: Hidestrand
authors: Department of Pediatrics, and Children's Research Institute, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors: Pippa
authors: P
authors: Simpson
authors: Department of Pediatrics, Division of Pediatric Cardiology, Pediatric Heart Center, UC Davis Children's Hospital, Sacramento, California; and.
authors: Andrew N
authors: AN
authors: Pelech
authors: Department of Cardiothoracic Surgery, the Heart Institute, Cincinnati Children's Hospital, Cincinnati, Ohio.
authors: James S
authors: JS
authors: Tweddell
authors: Department of Pediatrics, and Children's Research Institute, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors: D Woodrow
authors: DW
authors: Benson
authors: Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin Milwaukee, Wisconsin.
authors: John W
authors: JW
authors: Lough
authors: Department of Surgery, Division of Cardiovascular Surgery and Children's Research Institute, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors: Michael E
authors: ME
authors: Mitchell
mesh_terms: D000293:Adolescent; D024722:Cardiac Myosins / Q000235:genetics*; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000235:genetics; D005260:Female; D006801:Humans; D018636:Hypoplastic Left Heart Syndrome / Q000235:genetics*; D057026:Induced Pluripotent Stem Cells / Q000502:physiology; D008297:Male; D009154:Mutation / Q000235:genetics*; D032383:Myocytes, Cardiac / Q000502:physiology; D018995:Myosin Heavy Chains / Q000235:genetics*; D010375:Pedigree; D059467:Transcriptome / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
chemical_list: C094239:MYH6 protein, human; D024722:Cardiac Myosins; D018995:Myosin Heavy Chains
keywords: cardiomyocyte-autonomous; genetics; hypoplastic left heart syndrome; transplant-free survival outcome; upregulation of contractility genes