Contemporary Insights Into the Genetics of Hypertrophic Cardiomyopathy: Toward a New Era in Clinical Testing?

Mazzarotto, Francesco; Olivotto, Iacopo; Boschi, Beatrice; Girolami, Francesca; Poggesi, Corrado; Barton, Paul J.R.; Walsh, Roddy

doi:10.1161/jaha.119.015473

Cited by 50 publications

(63 citation statements)

References 133 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Determining the significance of rare HCM-associated variants or of incidental unexplained hypertrophy remains a key challenge of contemporary clinical genetics and cardiovascular medicine. 7 To determine the population prevalence of HCM-associated sarcomeric variants, characterise their phenotypic manifestations, estimate penetrance, and identify associations between sarcomeric variants and clinical outcomes, we performed an observational study of 218,813 adults in the UK Biobank (UKBB), of whom 200,584 have whole exome sequencing (WES). is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Outcomes and phenotypic expression of rare variants in hypertrophic cardiomyopathy genes amongst UK Biobank participants

Marvao

Zheng

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

BackgroundHypertrophic cardiomyopathy (HCM) is caused by rare variants in sarcomere-encoding genes, but little is known about the clinical significance of these variants in the general population.MethodsWe compared outcomes and cardiovascular phenotypes in UK Biobank participants with whole exome sequencing stratified by sarcomere-encoding variant status.ResultsThe prevalence of rare variants (allele frequency <0.00004) in HCM-associated sarcomere-encoding genes in 200,584 participants was 2.9% (n=5,727; 1 in 35), of which 0.24% (n=474, 1 in 423) were pathogenic or likely pathogenic variants (SARC-P/LP). SARC-P/LP variants were associated with increased risk of death or major adverse cardiac events compared to controls (HR 1.68, 95% CI 1.37-2.06, p<0.001), mainly due to heart failure (HR 4.40, 95% CI 3.22-6.02, p<0.001) and arrhythmia (HR 1.55, 95% CI 1.18-2.03, p=0.002). In 21,322 participants with cardiac magnetic resonance imaging, SARC-P/LP were associated with increased left ventricular maximum wall thickness (10.9±2.7 vs 9.4±1.6 mm, p<0.001) and concentric remodelling (mass/volume ratio: 0.63±0.12 vs 0.58±0.09 g/mL, p<0.001), but hypertrophy (≥13mm) was only present in 16% (n=7/43, 95% CI 7-31%). Other rare sarcomere-encoding variants had a weak effect on wall thickness (9.5±1.7 vs 9.4±1.6 mm, p=0.002) with no combined excess cardiovascular risk (HR 1.00 95% CI 0.92-1.08, p=0.9).ConclusionsIn the general population, SARC-P/LP variants have low aggregate penetrance for overt HCM but are associated with an increased risk of adverse cardiovascular outcomes and a sub-clinical cardiomyopathic phenotype. In contrast, rare sarcomeric variants that do not meet criteria to be classified as P/LP appear to have minimal clinical impact.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Outcomes and phenotypic expression of rare variants in hypertrophic cardiomyopathy genes amongst UK Biobank participants

Marvao

Zheng

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy in humans. More than 20 genes with 1,500 genetic variants have been identified over the last couple decades (1,2). Among these genes, mutations in the sarcomeric genes especially myosin heavy chain and myosin binding protein C genes are most commonly associated with HCM development in humans.…”

Section: Introductionmentioning

confidence: 99%

Heritability and Pedigree Analyses of Hypertrophic Cardiomyopathy in Rhesus Macaques (Macaca Mulatta)

et al. 2021

View full text Add to dashboard Cite

In a colony of rhesus macaques at California National Primate Research Center (CNPRC), naturally occurring hypertrophic cardiomyopathy (HCM) classified by left ventricular hypertrophy without obvious underlying diseases has been identified during necropsy over the last two decades. A preliminary pedigree analysis suggested a strong genetic predisposition of this disease with a founder effect. However, the mode of inheritance was undetermined due to insufficient pedigree data. Since 2015, antemortem examination using echocardiographic examination as well as other cardiovascular analyses have been performed on large numbers of rhesus macaques at the colony. Based on antemortem examination, HCM was diagnosed in additional 65 rhesus macaques. Using HCM cases diagnosed based on antemortem and postmortem examinations, the heritability (h2) was estimated to determine the degree of genetic and environmental contributions to the development of HCM in rhesus macaques at the CNPRC. The calculated mean and median heritability (h2) of HCM in this colony of rhesus macaques were 0.5 and 0.51 (95% confidence interval; 0.14–0.82), respectively. This suggests genetics influence development of HCM in the colony of rhesus macaques. However, post-translational modifications and environmental factors are also likely to contribute the variability of phenotypic expression. Based on the pedigree analysis, an autosomal recessive trait was suspected, but an autosomal dominant mode of inheritance with incomplete penetrance was also possible. Further investigation with more data from siblings, offspring, and parents of HCM-affected rhesus macaques are warranted. Importantly, the findings of the present study support conducting genetic investigations such as whole genome sequencing to identify the causative variants of inherited HCM in rhesus macaques.

show abstract

“…Heart Journal [2], is an important initiative designed to tackle this issue. While single-centre studies have provided some insights into genotype-phenotype correlation in HCM and the factors associated with clinical progression [3], the genetic and clinical heterogeneity of HCM limit the insights that can be achieved by this approach.…”

mentioning

confidence: 99%

“…The BIO FOr CARe (Identification of BIOmarkers of hypertrophic cardiomyopathy development and progression in Dutch MYBPC3 FOunder variant CARriers) cohort described in this issue of the Netherlands Heart Journal [ 2 ], is an important initiative designed to tackle this issue. While single-centre studies have provided some insights into genotype-phenotype correlation in HCM and the factors associated with clinical progression [ 3 ], the genetic and clinical heterogeneity of HCM limit the insights that can be achieved by this approach.…”

mentioning

confidence: 99%

Improving risk prediction in hypertrophic cardiomyopathy: the key role of Dutch founder variants

Walsh

Pinto

2021

Neth Heart J

View full text Add to dashboard Cite

Hypertrophic cardiomyopathy (HCM) is an important cardiac condition that can lead to sudden cardiac death (SCD) or heart failure in a subset of patients. Although HCM has been the subject of intense investigation for several decades now, our ability to predict disease onset and progression-in particular, to identify those patients at highest risk of severe clinical events-remains limited and represents one of the key challenges facing clinicians and researchers in this field. Genetic testing is a useful but blunt tool for risk prediction in HCM patients and their families. Causative rare variants in the index patient (identified in 30-50% of cases) enable cascade screening and the discharge from ongoing clinical surveillance of relatives without the variant.However, the factors that influence disease penetrance (which pathogenic variant carriers will develop the phenotype?) remain poorly understood, and asymptomatic genotype-positive individuals require regular and costly cardiac screening to monitor disease onset. While some risk prediction models are recommended for HCM patients, e.g. the HCM Risk-SCD calculator for prioritising patients who may benefit from prophylactic implantable cardioverter defibrillators [1], more comprehensive and accurate predictors of clinical severity are required.The BIO FOr CARe (Identification of BIOmarkers of hypertrophic cardiomyopathy development and progression in Dutch MYBPC3 FOunder variant CARriers) cohort described in this issue of the Netherlands

show abstract

Contemporary Insights Into the Genetics of Hypertrophic Cardiomyopathy: Toward a New Era in Clinical Testing?

Cited by 50 publications

References 133 publications

Outcomes and phenotypic expression of rare variants in hypertrophic cardiomyopathy genes amongst UK Biobank participants

Outcomes and phenotypic expression of rare variants in hypertrophic cardiomyopathy genes amongst UK Biobank participants

Heritability and Pedigree Analyses of Hypertrophic Cardiomyopathy in Rhesus Macaques (Macaca Mulatta)

Improving risk prediction in hypertrophic cardiomyopathy: the key role of Dutch founder variants

Contact Info

Product

Resources

About