Are Double Mutations Double Trouble?
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In this issue, Fourey et al1 report the results of genetic screening of 1411 patients with hypertrophic cardiomyopathy (HCM) who were seen in a multidisciplinary clinic during a 12-year period. Pathogenic or likely-pathogenic (P/LP) rare variants in an HCM-associated gene were identified in 272 cases (19%), 25 of whom (9% of genotype-positive individuals) were also found to carry a second rare variant. After stringent annotation of these additional variants using currently recommended criteria for pathogenicity,2 only 1 of the 25 individuals was deemed to have 2 P/LP variants (0.4% of genotype-positive individuals). This patient was diagnosed with HCM during adult life and succumbed to heart failure in the sixth decade. The clinical characteristics of the remaining 24 cases with 2 variants were compared with those of the 140 cases with a single variant, with no significant differences found in left ventricular wall thickness or age at diagnosis. These findings suggested that double mutations (with mutation defined here as a disease-causing rare variant) occur much less frequently than previously proposed.3,4 This study raises important questions about the criteria used to define pathogenicity of rare variants and the clinical implications of multiple variants.
See Article by Fourey et al
Fourey et al1 undertook a literature search and identified 15 HCM genetics studies that reported individuals with ≥1 rare variant. The cohort sizes ranged from 38 to 696 subjects, the number of genes tested ranged from 2 to 10, and 3% to 19% of genotype-positive individuals had 2 variants. Surprisingly, there was no apparent correlation between the number of double variant carriers and the number of genes screened, with a similar yield for studies that evaluated ≤5 genes (mean 8.7 individuals) and >5 genes (mean 9.1 individuals). Although Fourey et al1 evaluated substantially more patients than …