Meta-analysis of Penetrance and Systematic Review on Transition to Disease in Genetic Hypertrophic Cardiomyopathy.
Constantin-Cristian TopriceanuAlexandre da Costa PereiraJames C MoonGabriella CapturCarolyn Y HoPublished in: Circulation (2023)
Background: Hypertrophic cardiomyopathy (HCM) is characterized by unexplained left ventricular hypertrophy (LVH) 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, as penetrance (proportion of G+ who develop disease) is variable, age-dependent, and not reliably predicted. Methods: A systematic search of the literature was performed. We employed random effects generalized linear mixed model meta-analyses to contrast the cross-sectional prevalence and penetrance of sarcomere genes in two different contexts: clinically-based studies on patients and families with HCM versus population/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: 455 full text manuscripts were assessed. In family/clinical studies, the prevalence of sarcomere variants in patients diagnosed with HCM was 34%. The penetrance across all genes in non-proband relatives carrying P/LP variants identified during cascade screening was 57% (95% confidence interval [CI] [52,63]) and the mean age of HCM diagnosis was 38 years (95% CI [36, 40]). Penetrance varied from ~32% for myosin light chain ( MYL3 ) to ~55% for myosin binding protein C ( MYBPC3 ), ~60% troponin T ( TNNT2 ) and troponin I ( TNNI3 ), and ~65% for myosin heavy chain ( MYH7 ). 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; approximatively 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 age of ~16 years. However, short-term gene-specific phenotypic conversion varied between ~12% for MYBPC3 to ~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 understanding of true lifetime penetrance in families and in the community, and to identify drivers of the transition from subclinical to overt HCM.
Keyphrases
- hypertrophic cardiomyopathy
- left ventricular
- systematic review
- copy number
- genome wide
- meta analyses
- cross sectional
- binding protein
- case control
- end stage renal disease
- dna methylation
- newly diagnosed
- genome wide identification
- ejection fraction
- chronic kidney disease
- acute myocardial infarction
- cardiac resynchronization therapy
- heart failure
- risk factors
- mitral valve
- randomized controlled trial
- left atrial
- type diabetes
- magnetic resonance imaging
- mental health
- healthcare
- prognostic factors
- clinical trial
- magnetic resonance
- bioinformatics analysis
- patient reported outcomes
- transcatheter aortic valve replacement
- atrial fibrillation
- gene expression
- genome wide analysis