A malignant phenotype of hypertrophic cardiomyopathy caused by Arg719Gln cardiac beta-myosin heavy-chain mutation in a Chinese family

Mutations of the cardiac P-myosin heavy-chain (D-MHC) gene cause hypertroph ic cardiomyopathy (HCM). Recent genotype-phenotype correlation studies have shown that mutations carry prognostic significance. We studied five unrela ted Chinese families with hypertrophic cardiomyopathy. Exons 3-27 and 40 of the beta -MHC gene were screened with both the polymerase chain reaction-s ingle-strand conformation polymorphism (PCR-SSCP) method and the cycle sequ encing of the PCR products. A previously reported heterozygous mutation Arg 719Gln (arginine --> glutamine in codon 719) in exon 19 was found in one fa mily. The proband is a 30-year-old female diagnosed at age of 25 years when she presented with symptoms of chest pain, palpitations, and frequent inci dents of dizziness and syncope. A two-dimensional echocardiogram showed mod erate asymmetrical septal hypertrophy with left atrial enlargement. There w as no obstruction of the left ventricular outflow tract (LVOT). The patient also developed atrial fibrillation. The proband's mother and one of her si sters had similar clinical manifestations and both died suddenly at the age of 38 years. In addition, two silent nucleotide substitutions (ACT63ACC, T TT244TTC) in the cardiac beta -MHC gene were identified in the other four f amilies. These synonymous mutations did not cosegregate with the disease in the families and they were also present in the 60 healthy and age-matched control subjects. Of the five families studied, we did not find any missens e mutation in the remaining four families. The missense mutation Arg719Gln found in the Chinese family is associated with a malignant phenotype of sev ere symptoms and poor survival prognosis. This mutation also causes atrial enlargement and atrial fibrillation. Our study clinical provides further ev idence that the mutation, which alters the charge of the myosin heavy chain , is associated with a serious clinical outcome. (C) 2001 Elsevier Science BN. All rights reserved.