Abstract 10190: Double or Compound Sarcomere Mutations Associated with Sudden Death Risk in Hypertrophic Cardiomyopathy in the Absence of Conventional Risk Factors
Background: Risk stratification strategies employing sarcomere gene mutational analysis have proved imprecise in hypertrophic cardiomyopathy (HCM). Additional genetic risk markers that reliably identify patients predisposed to sudden death are needed. Whether multiple disease- causing sarcomere mutations can be regarded as markers for sudden death in the absence of other conventional risk factors is unresolved.
Methods: The databases of 3 HCM centers were assessed in Minneapolis, Boston and Sydney. From 2000-2010, HCM patients were identified who had undergone sudden death risk factor evaluation and in whom genetic testing had been performed for the 8 most common sarcomere genes.
Results: Of 330 HCM probands, 18 (5.5%) had 2 disease-causing mutations in genes encoding proteins of the cardiac sarcomere. Severe disease progression or adverse cardiovascular events occurred in 7 of these 18 patients (39%), including 3 patients (ages 31, 37, 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 one died. These 3 probands carried distinct and heterozygous disease-causing sarcomere mutations (including a man who inherited one mutation independently from each of his parents with HCM) - i.e., 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) sarcomere mutations appear to confer a gene dosage effect in HCM, predisposing patients to adverse disease progression. Multiple mutations were also associated with a risk of sudden death, even in the absence of conventional risk factors. These data suggest that genetic testing may contribute to the assessment of clinical course and prognosis among select HCM patients.
- © 2011 by American Heart Association, Inc.