Morphomechanic phenotypic variability of sarcomeric cardiomyopathies: A multifactorial polygenic perspective.
Morphology underlies subdivision of the primary/heritable sarcomeric cardiomyopathies (CMs) into hypertrophic (HCM) and dilated (DCM). Next-generation DNA-sequencing (NGS) has identified important disease-variants, improving CM diagnosis, management, genetic screening, and prognosis. Although monogenic (Mendelian) analyses directly point at downstream studies, they disregard coexisting genomic variations and gene-by-gene interactions molding detailed CM-phenotypes. In-place of polygenic models, in accounting for observed defective genotype-phenotype correlations, fuzzy concepts having gradations of significance and unsharp domain-boundaries are invoked, including pleiotropy, genetic-heterogeneity, incomplete penetrance, and variable expressivity. HCM and DCM undoubtedly entail cooperativity of unidentified/elusive causative genomic-variants. Modern genomics can exploit comprehensive electronic/digital health records, facilitating consideration of multifactorial variant-models. Genome-wide association studies entailing high-fidelity solid-state catheterization, multimodal-imaging, molecular cardiology, systems biology and bioinformatics, will decipher accurate genotype-phenotype correlations and identify novel therapeutic-targets, fostering personalized medicine/cardiology. This review surveys successes and challenges of genetic/genomic approaches to CMs, and their impact on current and future clinical care.
Duke Scholars
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Related Subject Headings
- Translational Research, Biomedical
- Sarcomeres
- Multifactorial Inheritance
- Humans
- Cardiovascular System & Hematology
- Cardiomyopathies
- Biomechanical Phenomena
- Biological Variation, Population
- 3208 Medical physiology
- 3201 Cardiovascular medicine and haematology
Citation
Published In
DOI
EISSN
Publication Date
Volume
Start / End Page
Location
Related Subject Headings
- Translational Research, Biomedical
- Sarcomeres
- Multifactorial Inheritance
- Humans
- Cardiovascular System & Hematology
- Cardiomyopathies
- Biomechanical Phenomena
- Biological Variation, Population
- 3208 Medical physiology
- 3201 Cardiovascular medicine and haematology