Minor hypertrophic cardiomyopathy genes, major insights into the genetics of cardiomyopathies

Walsh, Roddy; Offerhaus, Joost A.; Tadros, Rafik; Bezzina, Connie R.

doi:10.1038/s41569-021-00608-2

Cited by 66 publications

(47 citation statements)

References 92 publications

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“…Hypertrophy of the myocardium develops as an adaptive response to pressure or volume overload or can be the manifestation of a genetic disease [ 167 , 264 ]. In both scenarios, the hypertrophy may decompensate into heart failure, with or without preserved ejection fraction [ 26 ].…”

Section: Heart Failure Of Non-ischemic Originmentioning

confidence: 99%

Coronary blood flow in heart failure: cause, consequence and bystander

Heusch

2022

Basic Res Cardiol

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Heart failure is a clinical syndrome where cardiac output is not sufficient to sustain adequate perfusion and normal bodily functions, initially during exercise and in more severe forms also at rest. The two most frequent forms are heart failure of ischemic origin and of non-ischemic origin. In heart failure of ischemic origin, reduced coronary blood flow is causal to cardiac contractile dysfunction, and this is true for stunned and hibernating myocardium, coronary microembolization, myocardial infarction and post-infarct remodeling, possibly also for the takotsubo syndrome. The most frequent form of non-ischemic heart failure is dilated cardiomyopathy, caused by genetic mutations, myocarditis, toxic agents or sustained tachyarrhythmias, where alterations in coronary blood flow result from and contribute to cardiac contractile dysfunction. Hypertrophic cardiomyopathy is caused by genetic mutations but can also result from increased pressure and volume overload (hypertension, valve disease). Heart failure with preserved ejection fraction is characterized by pronounced coronary microvascular dysfunction, the causal contribution of which is however not clear. The present review characterizes the alterations of coronary blood flow which are causes or consequences of heart failure in its different manifestations. Apart from any potentially accompanying coronary atherosclerosis, all heart failure entities share common features of impaired coronary blood flow, but to a different extent: enhanced extravascular compression, impaired nitric oxide-mediated, endothelium-dependent vasodilation and enhanced vasoconstriction to mediators of neurohumoral activation. Impaired coronary blood flow contributes to the progression of heart failure and is thus a valid target for established and novel treatment regimens.

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Section: Heart Failure Of Non-ischemic Originmentioning

confidence: 99%

Coronary blood flow in heart failure: cause, consequence and bystander

Heusch

2022

Basic Res Cardiol

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“…While the zebrafish phenotypes suggested a RCM CMP, the embryos were not followed postnatally to determine if the phenotype evolved to the DCM or HCM phenotype. Also, genetic and phenotypic heterogeneity in CMP is quite common which could also account for variable CMP phenotypes between model organisms and humans, as well as between patients with the same gene defects 30 .…”

Section: Discussionmentioning

confidence: 99%

Whole genome sequencing delineates regulatory, copy number, and cryptic splice variants in early onset cardiomyopathy

et al. 2022

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Cardiomyopathy (CMP) is a heritable disorder. Over 50% of cases are gene-elusive on clinical gene panel testing. The contribution of variants in non-coding DNA elements that result in cryptic splicing and regulate gene expression has not been explored. We analyzed whole-genome sequencing (WGS) data in a discovery cohort of 209 pediatric CMP patients and 1953 independent replication genomes and exomes. We searched for protein-coding variants, and non-coding variants predicted to affect the function or expression of genes. Thirty-nine percent of cases harbored pathogenic coding variants in known CMP genes, and 5% harbored high-risk loss-of-function (LoF) variants in additional candidate CMP genes. Fifteen percent harbored high-risk regulatory variants in promoters and enhancers of CMP genes (odds ratio 2.25, p = 6.70 × 10−7 versus controls). Genes involved in α-dystroglycan glycosylation (FKTN, DTNA) and desmosomal signaling (DSC2, DSG2) were most highly enriched for regulatory variants (odds ratio 6.7–58.1). Functional effects were confirmed in patient myocardium and reporter assays in human cardiomyocytes, and in zebrafish CRISPR knockouts. We provide strong evidence for the genomic contribution of functionally active variants in new genes and in regulatory elements of known CMP genes to early onset CMP.

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“…There is also strong evidence of causality in three genes-PLN, FLNC [11,14,15], and recently ALPK3 [16] and moderate evidence of causality in five genes-CSRP3, TNNC1, ACTN2, JPH2, and FHOD3 [17,18]. For the other genes, evidence is weak or almost nonexistent [11,13,19]. Variants in genes encoding non-sarcomeric proteins account for a small percentage of patients with HCM.…”

Section: History Of Finding the Cause Of Hcmmentioning

confidence: 99%

Genetic Testing in Patients with Hypertrophic Cardiomyopathy

Bonaventura

Poláková

Vejtasová

et al. 2021

IJMS

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Hypertrophic cardiomyopathy (HCM) is a common inherited heart disease with an estimated prevalence of up to 1 in 200 individuals. In the majority of cases, HCM is considered a Mendelian disease, with mainly autosomal dominant inheritance. Most pathogenic variants are usually detected in genes for sarcomeric proteins. Nowadays, the genetic basis of HCM is believed to be rather complex. Thousands of mutations in more than 60 genes have been described in association with HCM. Nevertheless, screening large numbers of genes results in the identification of many genetic variants of uncertain significance and makes the interpretation of the results difficult. Patients lacking a pathogenic variant are now believed to have non-Mendelian HCM and probably have a better prognosis than patients with sarcomeric pathogenic mutations. Identifying the genetic basis of HCM creates remarkable opportunities to understand how the disease develops, and by extension, how to disrupt the disease progression in the future. The aim of this review is to discuss the brief history and recent advances in the genetics of HCM and the application of molecular genetic testing into common clinical practice.

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Minor hypertrophic cardiomyopathy genes, major insights into the genetics of cardiomyopathies

Cited by 66 publications

References 92 publications

Coronary blood flow in heart failure: cause, consequence and bystander

Coronary blood flow in heart failure: cause, consequence and bystander

Whole genome sequencing delineates regulatory, copy number, and cryptic splice variants in early onset cardiomyopathy

Genetic Testing in Patients with Hypertrophic Cardiomyopathy

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