Meta-Analysis of Penetrance and Systematic Review on Transition to Disease in Genetic Hypertrophic Cardiomyopathy

Abstract

Background: Hypertrophic cardiomyopathy (HCM) is characterized by unexplained left ventricular hypertrophy and is classically caused by pathogenic or likely pathogenic variants (P/LP) in genes encoding sarcomere proteins. Not all subclinical variant carriers will manifest clinically overt disease because penetrance (proportion of sarcomere or sarcomere-related P/LP variant carriers who develop disease) is variable, age dependent, and not reliably predicted.

Methods: A systematic search of the literature was performed. We used random-effects generalized linear mixed model meta-analyses to contrast the cross-sectional prevalence and penetrance of sarcomere or sarcomere-related genes in 2 different contexts: clinically-based studies on patients and families with HCM versus population or community-based studies. Longitudinal family/clinical studies were additionally analyzed to investigate the rate of phenotypic conversion from subclinical to overt HCM during follow-up.

Results: In total, 455 full-text manuscripts and articles were assessed. In family/clinical studies, the prevalence of sarcomere variants in patients diagnosed with HCM was 34%. The penetrance across all genes in nonproband relatives carrying P/LP variants identified during cascade screening was 57% (95% CI, 52%-63%), and the mean age at HCM diagnosis was 38 years (95% CI, 36%-40%). Penetrance varied from ≈32% for MYL3 (myosin light chain 3) to ≈55% for MYBPC3 (myosin-binding protein C3), ≈60% for TNNT2 (troponin T2) and TNNI3 (troponin I3), and ≈65% for MYH7 (myosin heavy chain 7). Population-based genetic studies demonstrate that P/LP sarcomere variants are present in the background population but at a low prevalence of <1%. The penetrance of HCM in incidentally identified P/LP variant carriers was also substantially lower at ≈11%, ranging from 0% in Atherosclerosis Risk in Communities to 18% in UK Biobank. In longitudinal family studies, the pooled phenotypic conversion across all genes was 15% over an average of ≈8 years of follow-up, starting from a mean of ≈16 years of age. However, short-term gene-specific phenotypic conversion varied between ≈12% for MYBPC3 and ≈23% for MYH7.

Conclusions: The penetrance of P/LP variants is highly variable and influenced by currently undefined and context-dependent genetic and environmental factors. Additional longitudinal studies are needed to improve our understanding of true lifetime penetrance in families and in the community and to identify drivers of the transition from subclinical to overt HCM.

Keywords: age of onset; cardiomyopathy, hypertrophic; penetrance.

Figure 1.

Pooled prevalence of P/LP sarcomere or sarcomere-related gene variants in clinical HCM cohorts. A, Prevalence in cohorts with ≥200 genotyped participants with hypertrophic cardiomyopathy (HCM), including probands. Smaller studies were excluded because they may introduce bias and potentially widen the CIs, affecting the precision of our results. B, Prevalence in studies that used the American College of Medical Genetics and Genomics (ACMG) criteria for variant classification. Neubauer et al 2019 used the Oxford Genetics Laboratory criteria, which closely follow the ACMG criteria, so that study was included in this analysis. GLMM indicates generalized linear mixed model; P/LP, pathogenic/likely pathogenic; and RE, random effects.

Figure 2.

MYBPC3 penetrance in cross-sectional family and clinically-based studies. A, After probands were excluded, cross-sectional penetrance (defined as the percent of sarcomere or sarcomere-related pathogenic or likely pathogenic variant carriers [G+] with left ventricular hypertrophy [LVH]) was calculated using a random-effects generalized linear mixed model (RE GLMM) meta-analysis, and the corresponding forest plot is shown. Overall, the pooled penetrance in G+ relatives in families with hypertrophic cardiomyopathy who were identified as part of cascade screening was 55% (95% CI, 49%–62%). B, We explored whether this estimate could have been influenced by the tendency to publish only certain types of results (eg, reporting a very high penetrance). This is not supported by the contour-enhanced funnel plot, given its symmetry. C, We explored whether the penetrance is influenced by sex (using percentage of males as a covariate) and geography by study continent through meta-regression. Although the meta-regression bubble plot suggests that including more males was associated with reporting a higher penetrance, this association was not significant. D, The reported penetrance was 56% (95% CI, 50%–62%) in studies from North America, 55% (95% CI, 47%–64%) from Europe, and 59% (95% CI, 46%–71%) from Asia. P values for pairwise comparisons are provided and indicate similar estimates across these geographic regions. MYBPC3 indicates myosin-binding protein C3.

Figure 3.

MYH7 penetrance in cross-sectional family and clinically-based studies. A, After probands were excluded, cross-sectional penetrance was calculated with a random-effects generalized linear mixed model (RE GLMM) meta-analysis, and the corresponding forest plot is shown. Overall, the pooled penetrance in relatives with sarcomere or sarcomere-related pathogenic or likely pathogenic variants (G+) in families with hypertrophic cardiomyopathy who were identified as part of cascade screening was 64% (95% CI, 53%–75%). B, We explored whether this estimate could have been influenced by the tendency to publish only certain types of results (eg, when reporting a very high penetrance). This is supported by the contour-enhanced funnel plot, given its asymmetry. C, We explored whether the penetrance is influenced by sex (using percentage of males as a covariate) and study continent through meta-regression. The meta-regression bubble plot does not suggest that including more males was associated with reporting a higher penetrance. D, The reported penetrance did not differ significantly by geography as represented by study continents, with values of P>0.05 for pairwise comparisons. LVH indicates left ventricular hypertrophy; and MYH7, myosin heavy chain 7.

Figure 4.

Phenotypic conversion for MYBPC3, MYH7, and TNNT2 genes in longitudinal studies. Phenotypic conversion (defined as the percentage of sarcomere or sarcomere-related pathogenic or likely pathogenic variant carriers [G+] who developed left ventricular hypertrophy [LVH] during longitudinal follow-up) was calculated with a random-effects generalized linear mixed model (RE GLMM) meta-analysis. The forest plots for MYBPC3 (A), MYH7 (B), and TNNT2 (C) genes are shown. Across all genes, the pooled phenotypic conversion was 15% over an average of ≈8 years of follow-up, starting from a mean age of ≈16 years. MYBPC3 indicates myosin-binding protein C3; MYH7, myosin heavy chain 7; and TNNT2, troponin T2.

Figure 5.

Prevalence and penetrance of P/LP variants in family compared with population studies. In clinical studies on patients and families with hypertrophic cardiomyopathy (HCM), the prevalence of pathogenic or likely pathogenic (P/LP) sarcomere variants was 34%, whereas the cross-sectional penetrance of HCM in relatives with P/LP was 57%. In contrast, in general population studies, the prevalence of P/LP variants in sarcomere genes was 50-fold lower (0.7%), and the cross-sectional penetrance in those incidentally identified as variant carriers was 5-fold lower (11%). In longitudinal family studies, the pooled phenotypic conversion across all genes was 15% over an average of ≈8 years of follow-up, starting from a mean age of ≈16 years. However, the phenotypic conversion in general population studies remains unknown. ARIC indicates Atherosclerosis Risk in Communities; MYBPC3, myosin-binding protein C3; MYH7, myosin heavy chain 7; and TNNT2, troponin T2.