Abstract 8867: High Risk of Cardiac Events in Hypertrophic Cardiomyopathy Patients With Double/Compound Heterozigosity
Background: Hypertrophic Cardiomyopathy (HCM) is myocardial disease caused by mutations of genes coding sarcomeric (sarcomeric HCM) and non sarcomeric proteins (non-sarcomeric HCM). When all known disease genes are systematically screened in consecutive patients a minority of cases shows double or compound heterozigosity. The prevalence of these latter cases is still provisional.
Purpose: We aimed at determining the prevalence of double or compound heterozigosity in a consecutive series of genotyped families with HCM and analyzing their outcome.
Methods: The clinical series is constituted of 188 unrelated probands and 307 mutated relatives. HCM was diagnosed according to the WHO criteria. Genetic testing was performed after counselling and written informed consent.
Results: Of 495 mutated individuals, 361 were affected and 134 healthy carriers. The mean age of affected members was significantly higher compared to those of the healthy carriers (34.3±15.2 versus 26.9±15.3 years, p=0.003). The molecular genetic analysis identified a pathologic mutation in one of the following disease genes: MYH7 (n=137), MYBPC3 (n=221), TNNT2 (n=29), TNNI3 (n=26), LAMP2 (n=3), PRKAG2 (n=3), tCAP (n=10), MYOZ2 (n=2), mtDNA (n=25). Moreover, 39 (8%) was found to carry a compound or double heterozigosity. After 87±65 months of follow-up, 79 (22%) phenotypically affected patients had one of the following events: CHF death while awaiting for HTx (n=12); HTx (n=20); appropriate ICD intervention plus HTx (n=4); sudden cardiac death or appropriate ICD intervention (n=43). None of the healthy carriers had events. According to the genotype, event distribution was: MYH7 (n=22/137, 16%); MYBPC3 (n= 25/221, 11%); TNNI3 (n= 7/26, 27%); TNNT2 (n= 5/29, 17%); double/compound heterozigosity (n= 13/39, 33%); LAMP2 (n=1/3, 33%); PRKAG2 (n= 1/3, 33%); mtDNA (n=6/25, 31%). The rate of cardiac events was significantly increased in patients with mtDNA or a double/compound heterozigosity (p= 0.02). No cardiac events were recorded in TCAP and MYOZ2 genotyped patients.
Conclusions: The prevalence of double/compound heterozygosity in our series was 8%. The rate of complications and malignant evolution was higher than in HCM associated with a single mutation.
- © 2010 by American Heart Association, Inc.