👤 Jesús Molano

Hypertrophic cardiomyopathy (HCM) is characterized by a heterogeneous presentation and clinical course. A minority of HCM patients develop end-stage HCM and require cardiac transplantation. The genetic basis of end-stage HCM is unknown but small series, isolated case reports and animal models have related the most aggressive heart failure course with the presence of multiple mutations. Twenty-six patients (age 40.4 ± 14.5 years; 46% male) transplanted for end-stage HCM underwent genetic screening of 10 HCM-related genes (MYH7, MYBPC3, TNNT2, TNNI3, TPM1, TNNC1, MYL3, MYL2, ACTC, LDB3). Additional genetic screening of LAMP2/PRKAG2 and mitochondrial DNA (mtDNA) was performed in four and three cases, respectively. Findings were correlated with clinical and histological features. Pathogenic mutations were identified in 15 patients (58%). Thirteen patients (50%) had mutations in sarcomeric genes (six in MYH7, three in MYBPC3, two in MYL2, one in TNNI3, and one in MYL3) and two patients had mutations in LAMP2. Only three patients (13%) had double mutations and all in homozygosis. Except for a more frequent family history of HCM, patients with mutations in sarcomeric genes did not show any clinical feature that distinguished them from patients without mutations in these genes. Evaluation of 44 relatives from 12 families identified 13 mutation carriers, 9 of whom had an overt HCM phenotype. Heart transplanted HCM has a heterogeneous genetic background where multiple mutations are uncommon. The clinical course of HCM is not primarily dependent on the presence of multiple sarcomeric mutations. Clinical and genetic evaluation of relatives does not support differential clinical management in HCM based on genetics. Show less

Hypertrophic cardiomyopathy is an autosomal dominant inherited disease characterized by ventricular hypertrophy and myofibril disarray. Mutations responsible for hypertrophic cardiomyopathy have been identified in 11 genes that encode for cardiac sarcomere proteins. Traditionally, hypertrophic cardiomyopathy due to mutation of the myosin-binding protein C gene (MYBPC3) has been thought to follow a benign course. We report a family with several members affected by hypertrophic cardiomyopathy in which there was a high incidence of sudden death. Disease was presumably caused by the substitution of cytosine by guanine at nucleotide 269 of MYBPC3 mRNA. This mutation, which has not previously been described, modifies codon 79, which encodes for the incorporation of a tyrosine, and gives rise to a stop codon. The mutation described here appears to confer a higher risk than that previously associated with hypertrophic cardiomyopathy due to MYBPC3 gene mutation. Show less