Double or compound sarcomere mutations in hypertrophic cardiomyopathy: a potential link to sudden death in the absence of conventional risk factors

Background: Risk stratification strategies employing sarcomere gene mutational analysis have proved imprecise in identifying high-risk patients with hypertrophic cardiomyopathy (HCM). Therefore, additional genetic risk markers that reliably determine which patients are predisposed to sudden death are needed.

Objective: The objective of this study was to determine whether multiple disease-causing sarcomere mutations can be regarded as markers for sudden death in the absence of other conventional risk factors.

Methods: Databases of 3 HCM centers were accessed, and 18 probands with 2 disease-causing mutations in genes encoding proteins of the cardiac sarcomere were identified.

Results: Severe disease progression or adverse cardiovascular events occurred in 7 of these 18 patients (39%), including 3 patients (ages 31, 37, and 57 years) who experienced sudden cardiac arrest but also were without evidence of conventional HCM risk factors; 2 survived with timely defibrillation and therapeutic hypothermia and 1 died. These 3 probands carried distinct and heterozygous disease-causing sarcomere mutations (including a man who inherited 1 mutation independently from each of his parents with HCM)-that is, double MYBPC3 and TNNI3 mutations and compound MYBPC3 mutations-as the only predisposing clinical markers evident to potentially explain their unexpected cardiac event.

Conclusions: These observations support the emerging hypothesis that double (or compound) mutations detected by genetic testing may confer a gene dosage effect in HCM, thereby predisposing patients to adverse disease progression. In 3 families, multiple sarcomere mutations were associated with a risk of sudden death, even in the absence of conventional risk factors.