Abstract 19436: Spectrum and Prevalence of Genetic Variation in Hypertrophic Cardiomyopathy-Susceptibility Genes Among Ostensibly Healthy Adults
Introduction: Hypertrophic cardiomyopathy (HCM) is characterized by unexplained asymmetric hypertrophy of the left ventricle and is the most prevalent genetic cardiovascular disease affecting 1 in 500 people. HCM-associated mutations localizing to nine genes that encode essential myofilaments of the cardiac sarcomere represent the most common genetic subtype of HCM known as sarcomeric/myofilament HCM. However, neither the spectrum nor the prevalence of genetic variation in ostensibly healthy adults has ever been systematically examined in these HCM-susceptibility genes.
Method: Using direct sequencing, the coding regions for MYH7, MYBPC3, MYL2, MYL3, TPM1, TNNT2, TNNI3, TNNC1, and ACTC were examined in 427 unrelated, ostensibly healthy adults of varied ethnicity (120 Asian, 110 black, 103 white, 42 Hispanic, and 52 other). Further, for all genes, amino acid conservation across 44 vertebrate species was compared for genetic variants found in Mayo Clinic diagnosed HCM cases vs. controls.
Results: A total of 52 distinct missense variants were identified among healthy controls including 11 variants (21%) that have been published previously as HCM-associated mutations: 8 in MYBPC3, 2 in MYH7, and 1 in MYL2. Of the 52 variants, 32 (62%) were observed only once and had not been identified previously in healthy adults. This suggests a background level of rare missense variation of approximately 7% (32/427). The two most common HCM-susceptibility genes, MYBPC3 and MYH7, also contributed the most background variation, 52% and 20%, respectively. Finally, case mutations in these 9 genes are more likely than control variants to affect amino acid positions without substitutions across species (55% vs. 23% respectively, p < 0.0001).
Conclusions: This study provides the first comprehensive study of the genetic variation of the sarcomeric genes associated with HCM in ostensibly healthy subjects. The identification of the background rate of genetic variation is critical in the interpretation of genetic testing. Conservation data across species in conjunction with other factors should help improve the signal to noise ratio for HCM genetic test interpretation.
- © 2010 by American Heart Association, Inc.