Genetics and genomics of dilated cardiomyopathy and systolic heart failure

Abstract

Heart failure is a major health burden, affecting 40 million people globally. One of the main causes of systolic heart failure is dilated cardiomyopathy (DCM), the leading global indication for heart transplantation. Our understanding of the genetic basis of both DCM and systolic heart failure has improved in recent years with the application of next-generation sequencing and genome-wide association studies (GWAS). This has enabled rapid sequencing at scale, leading to the discovery of many novel rare variants in DCM and of common variants in both systolic heart failure and DCM. Identifying rare and common genetic variants contributing to systolic heart failure has been challenging given its diverse and multiple etiologies. DCM, however, although rarer, is a reasonably specific and well-defined condition, leading to the identification of many rare genetic variants. Truncating variants in titin represent the single largest genetic cause of DCM. Here, we review the progress and challenges in the detection of rare and common variants in DCM and systolic heart failure, and the particular challenges in accurate and informed variant interpretation, and in understanding the effects of these variants. We also discuss how our increasing genetic knowledge is changing clinical management. Harnessing genetic data and translating it to improve risk stratification and the development of novel therapeutics represents a major challenge and unmet critical need for patients with heart failure and their families.

Calcium Signaling and Cardiac Arrhythmias

“…Mutations in over 30 genes can cause congenital DCM, and most of these genes encode proteins that are part of the sarcomere or are structural proteins needed to conduct mechanical force in the cardiomyocyte. 204 The remaining genes encode proteins that play various roles within cardiomyocytes to ensure proper contractile function. Various studies suggest that mutations in sarcomeric genes 205–207 as well as non-sarcomeric genes 208, 209 can alter Ca 2+ homeostasis, although the affected proteins are not directly involved in Ca 2+ -handling.…”

Exome sequencing identifies a FHOD3 p.S527del mutation in a Chinese family with hypertrophic cardiomyopathy

“…To investigate the cause of the clinical heterogeneity of the family, we performed additional analyses on the filtered exome sequencing data of the seven patients. A list of genes associated with cardiac hypertrophy or heart development was identified using the following criteria: (i) genes and closely related genes known to cause or contribute to cardiomyopathy and channelopathy (see Supporting information, Table S1); (ii) genes involved in heart development and morphogenesis (GO:0007507: heart development; GO:0003007: heart morphogenesis); and (iii) five polymorphisms involved in the renin–angiotensin–aldosterone system (RAAS). The five polymorphisms involved in RAAS were previously studied as disease modifiers in HCM, including rs4646994 in the angiotensin converting enzyme gene ( ACE ); rs5186 in the angiotensin II receptor type 1 gene ( AGTR1 ); rs1800875 in the cardiac chymase A gene ( CMA1 ); rs699 in the gene encoding angiotensinogen ( AGT ); and rs1799998 in the aldolase synthase gene ( CYP11B2 ).…”

“…Moreover, FHOD3 was associated with cardiomyopathy and was predicted to be deleterious. Sanger sequencing validated that the T A B L E 2 Clinical characteristcs of affected family members following criteria: (i) genes and closely related genes known to cause or contribute to cardiomyopathy and channelopathy 17,18 (see Supporting information, Table S1); (ii) genes involved in heart development and morphogenesis (GO:0007507: heart development;…”

Genetic determinants of heart failure: facts and numbers

“…DCM is most often autosomal‐dominantly inherited, and it is genetically highly heterogeneous 20, 21. Genes associated with DCM primarily encode for structural proteins in the cardiomyocyte sarcomere, cytoskeleton, and nuclear envelope and also for membrane ion channels and desmosomes 22. Of note, mutations in the genes MYH7 encoding beta myosin heavy chain, TNNT2 encoding troponin T, TTN encoding titin, and LMNA encoding a nuclear envelope protein are frequent causes of familial DCM 22…”

“…20,21 Genes associated with DCM primarily encode for structural proteins in the cardiomyocyte sarcomere, cytoskeleton, and nuclear envelope and also for membrane ion channels and desmosomes. 22 Of note, mutations in the genes MYH7 encoding beta myosin heavy chain, TNNT2 encoding troponin T, TTN encoding titin, and LMNA encoding a nuclear envelope protein are frequent causes of familial DCM. 22 TTN is the gene with the most exons in the human genome, and mutations are suggested to be most frequent with approximately 25%, 23,24 but it has to be taken into consideration that many of the described diseasecausing mutations in TTN might just be variants of unclear significance.…”