The Genetic Basis of Cardiomyopathies and Heart Failure 2022

Dear Colleagues,

The field of the genetics of cardiomyopathies and heart failure is evolving with breathtaking speed. Since the identification of the first disease-causing gene in any cardiomyopathy (the identification of the beta myosin heavy chain gene (MYH7) in hypertrophic cardiomyopathy (HCM) in 1989), a large number of genes have been linked to cardiomyopathies (CMPs). Over the last 20 years, candidate gene research studies assessing genes with a hypothetical role in CMPs implicated many additional genes. This process has been accelerated by the advent of novel DNA sequencing technologies (next-generation sequencing, NGS). However, it has become clear that sequencing expanded panels with an increasing number of genes offer limited additional detection sensitivity in terms of unequivocally causative genes. Beyond genes with definitive or moderate evidence for association with CMPs only a very small number of additional pathogenic variants can be found in other putative candidate genes. Although molecular genetics provided fundamental insights into the pathogenesis of CMPs, many open questions remained. Despite extensive interrogation by the next-generation sequencing of previously identified causative and candidate genes, only a small percentage of patients have identifiable mutation in coding regions or canonical splice-sites of causative genes. This relatively low sensitivity is a result of several factors. The etiology of “genotype-negative” CMPs (i.e., patients with no identifiable mutations) may still include rare variants in yet-unknown genes or in regulatory non-coding regions of known causative genes. Such genes are indeed reported but are responsible for only a small fraction of genotype-negative cases. Another possible explanation, at least with some evidence in HCM, may also be the presence of variants affecting cryptic splice-altering sites. Recently, data on the polygenic nature of HCM has also emerged.

Cardiomyopathies are rapidly entering  the field of personalized medicine. This is evidenced by the development of the first-in-class drug in HCM, the direct myosin inhibitor mavacamten, which has been specifically developed for the treatment of a hypercontractile sarcomere, a fundamental pathomechanism for HCM observed in experimental genetic models of HCM. Gene-based therapies, including exon skipping, trans-splicing, gene replacement and CRISPR/Cas9-based techniques have been developed and used successfully in animal models for HCM caused by MYBPC3 mutations. Therefore, apart from investigating novel genetic mechanisms for the pathomechanisms of CMP, the knowledge of the genetic basis of each patient with cardiomyopathies already seems to be of primary importance and clinical relevance.

This Special Issue of International Journal of Molecular Sciences focuses on the genetic basis of cardiomyopathies and heart failure, and welcomes both original research articles and review papers that deal with the molecular mechanisms underlying the role of molecular genetics in cardiomyopathies and heart failure.

Dr. Francesca Girolami
Prof. Dr. Róbert Sepp
Guest Editors

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• hypertrophic cardiomyopathy
• dilated cardiomyopathy
• arrhythmogenic (right ventricular)
• cardiomyopathy
• restrictive cardiomyopathy
• non-compact cardiomyopathy, left ventricular non-comapction
• tako-tsubo cardiomyopathy
• heart failure
• hypertrophic cardiomyopathy
• cardiomyopathy phenocopies
• inherited cardiomyopathy
• genetic mutation
• genetic mechanism
• molecular pathomechanism