Background-Available data suggests that double mutations in patients with hypertrophic cardiomyopathy are not rare and are associated with a more severe phenotype. Most of this data, however, is based on noncontemporary variant classification. Methods and Results-Clinical data of all hypertrophic cardiomyopathy patients with 2 rare genetic variants were retrospectively reviewed and compared with a group of patients with a single disease-causing variant. Furthermore, a literature search was performed for all studies with information on prevalence and outcome of patients with double mutations. Classification of genetic variants was reanalyzed according to current guidelines. In our cohort (n=1411), 9% of gene-positive patients had 2 rare variants in sarcomeric genes but only in 1 case (0.4%) were both variants classified as pathogenic. Patients with 2 rare variants had a trend toward younger age at presentation when compared with patients with a single mutation. All other clinical variables were similar. In data pooled from cohort studies in the literature, 8% of gene-positive patients were published to have double mutations. However, after reanalysis of reported variants, this prevalence diminished to 0.4%. All patients with 2 radical mutations in MYBPC3 in the literature had severe disease with death or heart transplant during the first year of life. Data on other specific genotype-phenotype correlations were scarce. Conclusions-Double mutations in patients with hypertrophic cardiomyopathy are much less common than previously estimated. With the exception of double radical MYBPC3 mutations, there is little data to guide clinical decision making in cases with double mutations. (Circ Cardiovasc

H ypertrophic cardiomyopathy (HCM) is the most commonly inherited monogenic cardiac disease with an estimated prevalence of 1:500.1 HCM is inherited as an autosomal dominant trait with a variable expression and age-related penetrance.2,3 In ≈35% to 60% of cases, HCM is caused by mutations in genes encoding sarcomere proteins. 4,5 To date, >1400 mutations in >13 genes have been identified, with the MYH7 (β-myosin heavy chain) and MYBPC3 (myosin-binding protein C) most commonly affected, accounting for >70% of genotyped families. 2,6See Editorial by Tower-Rader and Desai See Clinical PerspectiveAlthough thin-filament disease seems to have distinct phenotypic features in terms of left ventricular (LV) hypertrophy (LVH), cardiac magnetic resonance (CMR) late gadolinium enhancement (LGE) distribution, and diastolic abnormalities, 7 findings on the phenotypic differences between patients with MYH7 and MYBPC3 gene mutations have been inconsistent.Background-The 2 most commonly affected genes in hypertrophic cardiomyopathy (HCM) are MYH7 (β-myosin heavy chain) and MYBPC3 (β-myosin-binding protein C). Phenotypic differences between patients with mutations in these 2 genes have been inconsistent. Scarce data exist on the genotype-phenotype association as assessed by tomographic imaging using cardiac magnetic resonance imaging. Methods and Results-Cardiac magnetic resonance imaging was performed on 358 consecutive genotyped hypertrophic cardiomyopathy probands at 5 tertiary hypertrophic cardiomyopathy centers. Genetic testing revealed a pathogenic mutation in 159 patients (44.4%). The most common genes identified were MYH7 (n=53) and MYBPC3 (n=75); 33.1% and 47% of genopositive patients, respectively. Phenotypic characteristics by cardiac magnetic resonance imaging of these 2 groups were similar, including left ventricular volumes, mass, maximal wall thickness, morphology, left atrial volume, and mitral valve leaflet lengths (all P=non-significant). The presence of late gadolinium enhancement (65% versus 64%; P=0.99) and the proportion of total left ventricular mass (%late gadolinium enhancement; 10.4±13.2% versus 8.5±8.5%; P=0.44) were also similar. Conclusions-This multicenter multinational study shows lack of phenotypic differences between MYH7-and MYBPC3-associated hypertrophic cardiomyopathy when assessed by cardiac magnetic resonance imaging. Postmutational mechanisms appear more relevant to thick-filament disease expression and outcome than the disease-causing variant per se. (Circ Cardiovasc Imaging. 2017;10:e005311.

By provoking transient bradycardia followed by sinus tachycardia, this adenosine challenge test triggers QT changes that appear to be useful in distinguishing patients with LQTS from healthy controls.

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