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.

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

Graphical abstract

Figure 1

Phenotype in the Study Cohort During Follow-Up More than one-half of the subjects with an abnormal electrocardiogram (ECG) went on to develop overt hypertrophic cardiomyopathy (HCM). Those with an abnormal ECG but no overt HCM at the end of follow-up were younger, suggesting they will probably go on to develop overt HCM, although follow-up time from the first abnormal ECG was not clearly different between the 2 groups (∗p = 0.794). Ages reported are median (interquartile range). †At first abnormal ECG. ‡At first screening visit.

Central Illustration

Kaplan-Meier Estimates of Penetrance of Hypertrophic Cardiomyopathy in the Study Cohort by Sex Male sex and abnormal electrocardiogram are risk factors for penetrance of hypertrophic cardiomyopathy (HCM) in carriers of pathogenic/likely pathogenic variants in sarcomere genes, while TNNI3 variants are protective.

Figure 2

Kaplan-Meier Estimates of Penetrance of HCM in the Study Cohort By Causal Gene, ECG Phenotype, and Age at First Evaluation Penetrance is lowest in subjects with TNNI3 variants, compared to MYBPC3, MYH7, and TNNT2(A), was similar in adult and pediatric subjects (C), and an abnormal ECG was a strong predictor of subsequently developing overt HCM (B). Abbreviations as in Figure 1.

Figure 3

Utility of CMR for Screening Localized left ventricular hypertrophy involving the basal antero-septum and anterior wall in a 23-year-old man with a missense MYH7 mutation (p.Cys695Arg) with an electrocardiogram showing no clear pathological features (E). The hypertrophy can be appreciated on cardiac magnetic resonance (CMR) (A, B), but not on echocardiogram (C, D).