The role of noncoding genetic variants in cardiomyopathy

Abstract

Cardiomyopathies remain one of the leading causes of morbidity and mortality worldwide. Environmental risk factors and genetic predisposition account for most cardiomyopathy cases. As with all complex diseases, there are significant challenges in the interpretation of the molecular mechanisms underlying cardiomyopathy-associated genetic variants. Given the technical improvements and reduced costs of DNA sequence technologies, an increasing number of patients are now undergoing genetic testing, resulting in a continuously expanding list of novel mutations. However, many patients carry noncoding genetic variants, and although emerging evidence supports their contribution to cardiac disease, their role in cardiomyopathies remains largely understudied. In this review, we summarize published studies reporting on the association of different types of noncoding variants with various types of cardiomyopathies. We focus on variants within transcriptional enhancers, promoters, intronic sites, and untranslated regions that are likely associated with cardiac disease. Given the broad nature of this topic, we provide an overview of studies that are relatively recent and have sufficient evidence to support a significant degree of causality. We believe that more research with additional validation of noncoding genetic variants will provide further mechanistic insights on the development of cardiac disease, and noncoding variants will be increasingly incorporated in future genetic screening tests.

Advanced searching for hypertrophic cardiomyopathy heritability in real practice tomorrow

“…A vast majority of disease-associated variants (90%) that have been identified by GWAS reside within protein non-coding regions ( 102 ) and may be involved in regulating the expression of protein-coding genes and thereby contribute to the clinical manifestation of the diseases. By today, there is sufficient evidence that variants within promoter, enhancer, untranslated, splice, and intronic regions support a strong association with cardiomyopathies, including HCM [reviewed in ( 103 )]. Furthermore, according to ClinVar, a significant percentage of non-coding variants in splice sites (−60%) and UTRs (−5%), are classified as P or LP ( www.ncbi.nlm.nih.gov/clinvar ).…”

Anesthetic Management of Patients with Dilated Cardiomyopathy Undergoing Noncardiac Surgery

“…The etiology of dilated cardiomyopathy is complex and is generally considered to be caused by a combination of genetic and non-genetic factors. It was mentioned that familial DCM accounts for 30 to 50% of all DCM cases [ 10 , 11 ]. The main mode of inheritance of familial dilated cardiomyopathy is autosomal dominant inheritance, but there are also some familial cases showing mitochondrial mutation, autosomal recessive mutation, and X-linked recessive inheritance [ 12 ].…”