Abstract
Introduction: Hypertrophic cardiomyopathy (HCM) is clasically caused by pathogenic or likely pathogenic (P/LP) variants in genes encoding sarcomeric proteins (G+) leading to left ventricular hypertrophy (LVH). Aim: To contrast cross-sectional penetrance in clinical and population studies, and to determine the phenotypic conversion (% of G+ developing LVH during follow-up) in longitudinal studies ( Figure 1 ). Methods: A systematic literature search was performed. Pooled penetrance (with 95% confidence intervals [CIs]) and phenotypic conversion were calculated with random effects generalized linear mixed model meta-analyses. Calculations were made for each gene and across all genes. Meta-regression was employed to explore sex-related differences. Results: In cross-sectional clinical studies, after excluding probands, penetrance across all genes in relatives carrying P/LP variants identified during cascade screening was 58% (95% CI [53,64]). Penetrance varied from ~32% for myosin light chain 3 to ~65% for myosin heavy chain 7 ( MYH7 ) and troponin T ( TNNT2 ). The mean age of HCM onset was 38 years (95% CI [36, 40]) across all genes, but studies including a higher % of males reported a later age of onset. In contrast, penetrance in population studies was ~10-15%, ranging from 0% in Atherosclerosis Risk in Communities to 18% in the UK Biobank. In longitudinal clinical studies, the pooled phenotypic conversion was 15% (95% CI [8,27]) over an average of ~7 years of follow up, starting from a mean age of ~16 years across all genes. However, it varied from ~12% for myosin binding protein C to ~23% for MYH7 . Conclusions: The penetrance is 5-7-fold higher in a clinical context compared to incidental identification in population studies, suggesting important but currently undefined factors that modify disease expression. More longitudinal studies are needed to improve understanding of penetrance and identify drivers of the transition from genetic susceptibility to overt HCM
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