Systematic Review of Penetrance in Genetic Hypertrophic Cardiomyopathy

Quick Takes

  • The penetrance of a pathogenic/likely pathogenic (P/LP) sarcomeric mutation is low in the general population at 11% but five-fold higher at 57% in patients with HCM and their family members.
  • Geographical variability was noted in disease penetrance with variability by gene.
  • There are nongenetic factors that influence disease penetrance of individuals with sarcomeric P/LP mutations.

Study Questions:

What is the prevalence and penetrance of sarcomeric genes in clinical studies with patients and families with hypertrophic cardiomyopathy (HCM) as compared with population-based studies of asymptomatic individuals?


The authors conducted a systematic review of six databases to identify two subsets of studies that assessed the prevalence and penetrance of pathogenic/likely pathogenic (P/LP) variants. This included 1) clinically based, cross-sectional studies on patients with HCM and their families (pooled n = 20,808 participants), and 2) general population-based longitudinal studies (n = 1,397 with P/LP variants among 213,911 genotypes participants). Population studies were also analyzed to assess the rate of phenotypic conversion from subclinical to overt HCM at follow-up and included ARIC (Atherosclerosis Risk in Communities), Framingham Heart Study, Jackson Heart Study, and UK Biobank.


Database searches identified 1,734 articles, narrowed to 115 that met inclusion criteria for analysis. Based on the American College of Medical Genetics criteria, a P/LP variant was identified in 34% of patients with HCM in family/clinical studies. In these studies, penetrance differed from gene to gene (range 32%-65%) with a pooled penetrance of 57%. If probands (earliest affected family member) were included, penetrance increased to 67% but again with gene-to-gene variation. Mean age of HCM diagnosis was 38 years across all genes. The most commonly involved sarcomeric genes for HCM pooled penetrance were 55% for MYBPC3 (myosin-binding protein C3), 64% for MYH7 (myosin heavy chain 7), and 62% for TNNT2 (troponin T2). The lowest pooled penetrance was noted as 32% for MYL3 (myosin light chain 3) and 38% for CSRP-3 (cysteine- and glycine-rich protein 3). There were no sex-related differences in overall or gene-specific penetrance. Penetrance varied by geography with highest penetrance noted in Asia followed by North America.

In longitudinal population-based studies, the pooled prevalence for a P/LP sarcomeric variant was 0.7% in the general population. Pooled penetrance of P/LP variant was 11% (ranged from 0% in ARIC to 18% in UK Biobank). Due to variability in how HCM was defined across these cohorts, a meta-analysis was not performed. The pooled phenotypic conversion rate (i.e., genotype+ but phenotype– progressing to phenotype+) across all genes was 15% over an average follow-up of 8 years starting at age 16, but there was substantial heterogeneity.


In a systematic review, the pooled prevalence of P/LP sarcomeric gene was 50 times higher in clinical cohorts of families and patients with HCM than in the general population of asymptomatic individuals. The penetrance was five-fold higher in the clinical cohort of HCM families and patients compared with population-based studies.


Genetic testing identifies P/LP sarcomeric mutations in about 60% patients with familial HCM. However, not all genotype+ patients manifest the disease. To date, longitudinal population-based and cross-sectional studies of HCM families that have attempted to explore penetrance of HCM have been limited by small sample size. In this systematic review, the authors pooled two separate cohorts of patients—one including clinical cohorts comprised of patients with HCM or their family members and the other including population cohorts of asymptomatic individuals.

The authors noted that P/LP variants have a very low prevalence in the general population. However, the penetrance of P/LP sarcomeric variants was over five-fold higher in the clinical cohort comprised of HCM patients and their families compared with the population-based cohort. Furthermore, penetrance was highly variable by gene. Most interestingly though, while there was no sex-based difference in penetrance, there was geographical variability in penetrance.

These observations highlight that there are nongenetic factors that influence disease penetrance in HCM. They also suggest that a family member of an HCM patient represents a higher-risk patient than an individual noted to have a P/LP sarcomeric mutation on incidental testing. These results should, however, take into account high heterogeneity in included studies.

Clinical Topics: Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, Genetic Arrhythmic Conditions

Keywords: Genetics, Cardiomyopathy, Hypertrophic

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