Compound and double mutations in patients with hypertrophic cardiomyopathy: implications for genetic testing and counselling

Objective: To report the frequency of single and multiple gene mutations in an Australian cohort of patients with hypertrophic cardiomyopathy (HCM). Methods: Genetic screening of seven HCM genes (beta-MHC, MyBP-C, cTnT, cTnI, ACTC, MYL2, and MYL3) was undertaken in 80 unrelated probands. Screening was by denaturing high performance liquid chromatography and direct DNA sequencing. Clinical data were collected on all patients and on genotyped family members. Results: 26 mutations were identified in 23 families (29%). Nineteen probands (24%) had single mutations (11 beta-MHC, 4 MyBP-C, 3 cTnI, 1 cTnT). Multiple gene mutations were identified in four probands (5%): one had a double mutation and the others had compound mutations. Six of 14 affected individuals from multiple mutation families (43%) experienced a sudden cardiac death event, compared with 10 of 55 affected members (18%) from single mutation families (p = 0.05). There was an increase in septal wall thickness in patients with compound mutations (mean (SD): 30.7 (3.1) v 24.4 (7.4) mm; p<0.05). Conclusions: Multiple gene mutations occurring in HCM families may result in a more severe clinical phenotype because of a "double dose" effect. This highlights the importance of screening the entire panel of HCM genes even after a single mutation has been identified.