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Nat Biomed Eng. 2019 Feb;3(2):147-157. doi: 10.1038/s41551-019-0348-9. Epub 2019 Feb 7.

Combinatorial interactions of genetic variants in human cardiomyopathy.

Author information

1
Division of Cardiology, Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
2
Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA.
3
Veterans Administration Healthcare San Diego, San Diego, CA, USA.
4
Department of Neuroscience, The Scripps Research Institute, La Jolla, CA, USA.
5
Department of Human Biology, J. Craig Venter Institute, La Jolla, CA, USA.
6
Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA. aengler@ucsd.edu.
7
Sanford Consortium for Regenerative Medicine, La Jolla, CA, USA. aengler@ucsd.edu.
8
Division of Cardiology, Department of Medicine, University of California, San Diego, La Jolla, CA, USA. rross@ucsd.edu.
9
Veterans Administration Healthcare San Diego, San Diego, CA, USA. rross@ucsd.edu.
10
Division of Cardiology, Department of Medicine, University of California, San Diego, La Jolla, CA, USA. nchi@ucsd.edu.
11
Institute of Genomic Medicine, University of California, San Diego, La Jolla, CA, USA. nchi@ucsd.edu.

Abstract

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.

PMID:
30923642
PMCID:
PMC6433174
[Available on 2020-02-01]
DOI:
10.1038/s41551-019-0348-9

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