Phenotype–Genotype Correlation in Hypertrophic Cardiomyopathy
Less Signal, More Noise?
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Identification of a genetic basis for hypertrophic cardiomyopathy (HCM) has proven to be more complex than originally postulated. Early reports in the 1950s and 1960s of clusters of patients within families with left ventricular hypertrophy (LVH), cardiac myocyte disarray, and fibrosis, as well as symptoms of heart failure and sudden cardiac death, with what seemed to be caused by an autosomal dominant pattern of inheritance, led to initial excitement regarding genetic testing in the 1990s.1 Although initial attempts to identify candidate genes led to the seminal discoveries of discrete mutations in the MYH7 (β-myosin heavy chain), which segregated within affected individuals in families,2 these mutations were not present in all families with HCM. Further analysis of affected families led to the identification of mutations in genes for other sarcomere proteins including other thick filaments (MYL2 [regulatory myosin light chain] and MYL3 [essential myosin light chain]), thin filaments (TNNT2 [cardiac troponin T], TNNI3 [cardiac troponin I], TNNC1 [cardiac troponin C], TPM-1 [α-tropomyosin], and ACTA [α-cardiac actin]), MYBPC3 (cardiac myosin-binding protein c), and z-disc proteins (ACTN2 [α-actinin 2] and MYOZ2 [myozenin 2]).1 At this point, >1400 mutations in 11 sarcomere protein genes have been identified, although ≈50% of identified mutations are in MYH7 or MYBPC3.3 Although the majority of mutations are private mutations within a family or as a de novo mutations, there are some HCM gene mutations referred to as founder mutations, which are highly conserved within populations that often have been historically geographically or culturally isolated. These occur almost exclusively in the MYBPC3 gene resulting in a truncated protein and delayed penetrance until after the reproductive years.1,4 At present, genetic testing identifies a known pathogenic or presumed pathogenic mutation in ≈30% to 40% of patients with phenotypic HCM. Both the Toronto Genotype score …