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Combinatorial interactions of genetic variants in human cardiomyopathy
- Source :
- Nature Biomedical Engineering. 3:147-157
- Publication Year :
- 2019
- Publisher :
- Springer Science and Business Media LLC, 2019.
-
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.
- Subjects :
- 0301 basic medicine
Genetics
Biomedical Engineering
Medicine (miscellaneous)
Bioengineering
TPM1
Heritability
Biology
musculoskeletal system
Penetrance
Computer Science Applications
03 medical and health sciences
030104 developmental biology
0302 clinical medicine
Genetic variation
cardiovascular system
CRISPR
cardiovascular diseases
Expressivity (genetics)
Allele
Gene
030217 neurology & neurosurgery
Biotechnology
Subjects
Details
- ISSN :
- 2157846X
- Volume :
- 3
- Database :
- OpenAIRE
- Journal :
- Nature Biomedical Engineering
- Accession number :
- edsair.doi...........11bc4ff4d7f76c051db5624ce2c23dd6