A Novel MYH6 E1503V Variant in a Family with a History of Heart Disease, including Hypoplastic Left Heart Syndrome

Hypoplastic Left Heart Syndrome (HLHS) is a severe form of congenital heart disease (CHD), requiring prompt surgical intervention and eventual transplant. Despite significant advances in detection and treatment of HLHS, genetic risk factors have been identified in <5% of patients. Our prior studies of 190 HLHS patients identified 19 distinct, rare variants in the gene encoding for a‐myosin heavy chain ( MYH6 ), with variant carriers exhibiting reduced transplant‐free survival (p < 1 × 10 −3 ). In‐depth genetic analysis was performed on the family of one HLHS subject who exhibited a novel E1503V variant in the tail domain of MYH6 . The variant was identified in six additional members of the family, all of whom were related to the proband via the maternal grandmother. Four of those individuals also exhibited adult heart disease, with varying ages of onset. Though MYH6 variants have been implicated in a number of heart diseases – including arrhythmias, familial cardiomyopathies, as well as various forms of CHD – to our knowledge this is the first association of a single variant with both adult heart disease and HLHS. α‐myosin heavy chain (α‐MHC) is a cardiac‐specific protein that functions as a component of the sarcomere, the major contractile unit of the heart muscle. We therefore sought to evaluate functional consequences of MYH6 E1503V on a‐MHC in vitro . Using CRISPR‐Cas9 gene editing technology, we successfully introduced the variant into induced pluripotent stem cells (iPSCs) from an unrelated individual, which were then used to generate cardiomyocytes. Subsequent evaluation of these cells revealed key insights into the effect of MYH6 E1503V on sarcomere organization and contractile properties in cardiomyocytes, as well as their proliferation and differentiation capacity. Support or Funding Information Children's Research Institute at the Children's Hospital of Wisconsin, Little Hearts for Life Foundation, M.A is a member of the Medical Scientist Training Program at MCW, which is partially supported by a training grant from NIGMS T32‐GM080202 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .