Combinatorial interactions of genetic variants in human cardiomyopathy

• DOI: 10.1038/s41551-019-0348-9
• Publication Date: 2019-02-07T17:09:11Z
• Authors: Dekker C. Deacon; Cassandra L. Happe; Chao Chen; Neil Tedeschi; Ana Maria Manso; Ting Li; Nancy D. Dalton; Qian Peng; Elie N. Farah; Yusu Gu; Kevin P. Tenerelli; Vivien D. Tran; Ju Chen; Kirk L. Peterson; Nicholas J. Schork; Eric D. Adler; Adam J. Engler; Robert S. Ross; Neil C. Chi
• Keywords: Cardiomyopathy, Dilated; Male; Pluripotent Stem Cells; 0301 basic medicine; Cardiomyopathy; Biomedical Engineering; Inheritance Patterns; 610; Cardiovascular; Models, Biological; Mice; 03 medical and health sciences; Engineering; Rare Diseases; Models; Dilated; Genetics; 2.1 Biological and endogenous factors; Animals; Humans; Genetic Predisposition to Disease; Myocytes, Cardiac; Stem Cell Research - Embryonic - Human; Myocytes; Stem Cell Research - Induced Pluripotent Stem Cell - Human; Stem Cell Research - Induced Pluripotent Stem Cell; Human Genome; Genetic Variation; Stem Cell Research; Biological; 3. Good health; Extracellular Matrix; Pedigree; Up-Regulation; Heart Disease; Good Health and Well Being; Gene Expression Regulation; Female; Generic health relevance; Cardiac; Biomedical engineering; Biotechnology; Muscle Contraction

Dilated cardiomyopathy (DCM) is a leading cause of morbidity and mortality worldwide; yet how genetic variation and environmental factors impact DCM heritability remains unclear. Here, we report that compound genetic interactions between DNA sequence variants contribute to the complex heritability of DCM. By using genetic data from a large family with a history of DCM, we discovered that heterozygous sequence variants in the TROPOMYOSIN 1 (TPM1) and VINCULIN (VCL) genes cose-gregate in individuals affected by DCM. In vitro studies of patient-derived and isogenic human-pluripotent-stem-cell-derived cardio-myocytes that were genome-edited via CRISPR to create an allelic series of TPM1 and VCL variants revealed that cardiomyocytes with both TPM1 and VCL variants display reduced contractility and sarcomeres that are less organized. Analyses of mice genetically engineered to harbour these human TPM1 and VCL variants show that stress on the heart may also influence the variable penetrance and expressivity of DCM-associated genetic variants in vivo. We conclude that compound genetic variants can interact combinatorially to induce DCM, particularly when influenced by other disease-provoking stressors.