Abstract 2725: Phenotype Heterogeneity In A Consecutive Series Of Genotyped Patients Diagnosed With Hypertrophic Cardiomyopathy
MYBPC3 gene defects are associated with late-onset, mild left ventricular hypertrophy, low risk of sudden death, good prognosis; MYH7 gene defects are more severe. The study aimed at describing the clinical phenotype of a consecutive series of 108 unrelated genotyped probands diagnosed with hypertrophic cardiomyopathy and 344 family members. MYH7, MYBPC3, TNNT2, TNNI3, alpha-TPM, tCAP, PRKAG2 and LAMP2 gene were routinely screened. Of 451 members of 108 families, 288 were genotypically affected (63.8%): 194 were phenotypically affected and 94 were phenotypically healthy. Of the 288 mutated individuals, 265 (92%) carried a single mutation in one of the analysed genes while 23 individuals (8%, all affected) carried a compound or double heterozigosity. The mean age of affected members was significantly higher compared to that of healthy carriers (34.8 ± 17.2 vs. 28.5 ± 16.3 years, p = 0.004). In the 108 probands, we identified 86 pathologic mutations; 22 mutations recurred in more than one family. The distribution of the mutation/gene was: 79 MYH7 ( 27%), 146 MYBPC3 (51%), 16 TNNT2 (5.5%), 10 TNNI3 (3.5%), 3 LAMP2 (1%), 3 PRKAG2 (1%), 9 tCAP (3%). Double or compound heterozygous included 10 patients with a MYBPC3 plus a MYH7 gene mutations, 10 double MYBPC3 heterozygotes, and three MYH7 plus a known severe mitochondrial DNA mutation. All genotyped individuals were followed up for 90 ± 70 months. In patients with single mutations of MYH7 and MYBPC3 the severity of the hypertrophy was similar (19 ± 7 mm versus 19 ± 4.5mm, p = NS). The number of events recorded in the two groups was similar: 11 (14%) events [sudden cardiac death: n = 3; heart transplant: n = 5; congestive heart failure death: n = 1; ICD appropriate intervention: n = 1; ICD appropriate intervention plus heart transplant: n = 1] in MYH7 mutation carriers versus 23 (15.7%, p = ns) [sudden cardiac death: n = 10; congestive heart failure death: n = 2; heart transplant: n = 1; appropriate ICD intervention: n = 9; appropriate ICD intervention plus heart transplant: n = 1] in MYBPC3 gene mutation carriers. In our study, MYBPC3 was the most frequent disease gene. The percentage of double or compound heterozigosity was 8%. Maximal wall thicknesses and rate of events were similar in carriers of mutations of the two major candidate genes.