Penetrance of Hypertrophic Cardiomyopathy in Sarcomere Protein Mutation Carriers

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.

Phenotypic Expression and Outcomes in Individuals With Rare Genetic Variants of Hypertrophic Cardiomyopathy

“…SARC-HCM-P/LP variants were associated with a greater increase in lifetime risk of death and MACE in female subjects than in male subjects. This supports findings in patients with HCM, in whom, despite apparent reduced disease penetrance ( 33 ), women have lower survival regardless of genotype ( 34 , 35 ). In contrast, SARC-IND variants (which include a mixture of variants with potential to cause HCM, DCM, or have little impact on cardiomyopathy risk) express a minimal phenotype in aggregate and have a generally benign clinical course.…”

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

“…2 SARC-P/LP variants, were associated with a greater increase in lifetime risk of death and MACE in females than in males. This supports findings in HCM patients, where despite apparent reduced disease penetrance, 28 women have lower survival, regardless of genotype. 29,30 In contrast, SARC-IND variant carriers, which include a mixture of benign variants and variants with pathogenic potential, express a minimal phenotype and have a generally benign clinical course.…”

Sex Differences in Hypertrophic Cardiomyopathy: Interaction With Genetics and Environment

“…They found that disease penetrance in those ≤ 40 years of age was 92% in males and 67% in females. Another retrospective study of sarcomere variant carriers found that male sex and an abnormal ECG are associated with a higher risk of developing HCM [27]. The underlying mechanisms for sex-based differences in the penetrance and expression of sarcomeric HCM are not well understood.…”