Penetrance of Hypertrophic Cardiomyopathy in Sarcomere Protein Mutation Carriers

J Am Coll Cardiol. 2020 Aug 4;76(5):550-559. doi: 10.1016/j.jacc.2020.06.011.

Abstract

Background: Predictive genetic screening of relatives of patients with hypertrophic cardiomyopathy (HCM) caused by sarcomere protein (SP) gene mutations is current standard of care, but there are few data on long-term outcomes in mutation carriers without HCM.

Objectives: The aim of this study was to determine the incidence of new HCM diagnosis in SP mutation carriers.

Methods: This was a retrospective analysis of adult and pediatric SP mutation carriers identified during family screening who did not fulfill diagnostic criteria for HCM at first evaluation.

Results: The authors evaluated 285 individuals from 156 families (median age 14.2 years [interquartile range: 6.8 to 31.6 years], 141 [49.5%] male individuals); 145 (50.9%) underwent cardiac magnetic resonance (CMR). Frequency of causal genes was as follows: MYBPC3 n = 123 (43.2%), MYH7 n = 69 (24.2%), TNNI3 n = 39 (13.7%), TNNT2 n = 34 (11.9%), TPM1 n = 9 (3.2%), MYL2 n = 6 (2.1%), ACTC1 n = 1 (0.4%), multiple mutations n = 4 (1.4%). Median follow-up was 8.0 years (interquartile range: 4.0 to 13.3 years) and 86 (30.2%) patients developed HCM; 16 of 50 (32.0%) fulfilled diagnostic criteria on CMR but not echocardiography. Estimated HCM penetrance at 15 years of follow-up was 46% (95% confidence interval [CI]: 38% to 54%). In a multivariable model adjusted for age and stratified for CMR, independent predictors of HCM development were male sex (hazard ratio [HR]: 2.91; 95% CI: 1.82 to 4.65) and abnormal electrocardiogram (ECG) (HR: 4.02; 95% CI: 2.51 to 6.44); TNNI3 variants had the lowest risk (HR: 0.19; 95% CI: 0.07 to 0.55, compared to MYBPC3).

Conclusions: Following a first negative screening, approximately 50% of SP mutation carriers develop HCM over 15 years of follow-up. Male sex and an abnormal ECG are associated with a higher risk of developing HCM. Regular CMR should be considered in long-term screening.

Keywords: ECG; cardiac magnetic resonance; echocardiogram; sex; sudden cardiac death.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Cardiac Myosins / genetics*
  • Cardiac Myosins / metabolism
  • Cardiomyopathy, Hypertrophic / diagnosis
  • Cardiomyopathy, Hypertrophic / genetics*
  • Cardiomyopathy, Hypertrophic / metabolism
  • Child
  • DNA / genetics*
  • DNA Mutational Analysis
  • Echocardiography
  • Female
  • Follow-Up Studies
  • Genetic Testing / methods*
  • Heterozygote
  • Humans
  • Male
  • Mutation*
  • Pedigree
  • Retrospective Studies
  • Sarcomeres / genetics
  • Sarcomeres / metabolism*
  • Young Adult

Substances

  • DNA
  • Cardiac Myosins