Circulation, Vol 86, 345-352, Copyright © 1992 by American Heart Association
ND Epstein, GM Cohn, F Cyran and L Fananapazir
BACKGROUND. The disease gene for hypertrophic cardiomyopathy (HCM) has been
identified as the beta-myosin heavy chain (beta-MHC) gene in some HCM
families. We describe extensive clinical evaluations in two kindreds with
two distinct point mutations in the beta-MHC gene. METHODS AND RESULTS. We
used single-strand confirmation polymorphism (SSCP) gel analysis of
polymerase chain reaction-amplified products capturing each of the 40
beta-MHC gene exons to identify distinct missense mutations in two HCM
kindreds. Clinical, ECG, and echocardiographic studies were performed in
the two kindreds: kindred 2755 with amino acid 908Leu----Val mutation and
kindred 2002 with amino acid 403Arg----Gln mutation. The morphological
appearances of HCM were similar in these two kindreds. However, the two
kindreds differed with respect to disease penetrance, age of onset of
disease, and incidence of premature sudden death. Twelve of 31 adults
(greater than or equal to 17 years) with the disease gene in kindred 2755
did not have left ventricular hypertrophy (LVH), and only five of these had
ECG abnormalities. Thus, the disease penetrance in adults with this
mutation was only 61%. None of 11 children aged less than 16 years had LVH.
The 908 mutation was associated with a low incidence of cardiac events:
Only two sudden deaths and one syncope occurred in 46 individuals with the
mutant allele. In contrast, LVH was present in all 11 adults in kindred
2002 with the 403 mutation (100% disease penetrance). In addition, three of
four affected children were symptomatic and had clinical evidence of HCM.
The disease in this kindred was severe and resulted in six premature sudden
deaths. Seven additional patients had syncope or presyncope. CONCLUSIONS.
In some kindreds, the HCM disease gene is more prevalent than indicated by
echocardiography and ECG. Some point mutations may be associated with a
more malignant prognosis. Preclinical identification of children with
mutations associated with a high incidence of sudden death and syncope
provides the opportunity to evaluate efficacy of early therapeutic
interventions.
ARTICLES
Differences in clinical expression of hypertrophic cardiomyopathy associated with two distinct mutations in the beta-myosin heavy chain gene. A 908Leu----Val mutation and a 403Arg----Gln mutation
Clinical Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.
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