Circulation, Vol 89, 22-32, Copyright © 1994 by American Heart Association
L Fananapazir and ND Epstein
BACKGROUND: We have previously described two distinct mutations in the
beta-myosin heavy chain gene with markedly different clinical presentations
and outcome: The 908Leu-->Val mutation was associated with a low disease
penetrance and a benign prognosis. In contrast, the 403Arg-->Gln
mutation in a Caucasian kindred was associated with a 100% disease
penetrance and high incidence of sudden cardiac death. Recently, another
mutation, 606Val-->Met, has been reported to be associated with "near
normal survival" and offered as evidence for the benign nature of neutral
charge substitutions. METHODS AND RESULTS: We report (1) a large kindred
(245 family members at risk of inheriting the disease gene) with a
256Gly-->Glu mutation characterized by a similar disease penetrance in
adults and in children (56% and 60%, respectively) and a cumulative sudden
cardiac death rate of only 2% at 50 years of age, (2) a kindred with the
606Val-->Met mutation with four sudden cardiac deaths in eight affected
individuals, and (3) a Korean kindred with the 403Arg-->Gln mutation.
Although the disease occurred early and was associated with a high
prevalence of myocardial ischemia in both of our kindreds with the
403Arg-->Gln mutation, no sudden cardiac death or syncope has occurred
in the Korean kindred. Furthermore, in the Caucasian kindred, all patients
had nonobstructive hypertrophic cardiomyopathy, but most of the patients in
the Korean kindred had left ventricular outflow obstruction. CONCLUSIONS:
The conclusions are as follows: (1) Although several sudden cardiac deaths
are sufficient to establish that a mutation is malignant, study of a large
kindred is necessary to be certain that a mutation is benign. To date, only
the 908Leu-->Val and the 256Gly-->Glu mutations satisfy this
requirement. (2) The 256Gly-->Glu mutation demonstrates that not all
mutations that result in a charge change are malignant. (3) Conversely, the
606Val-->Met mutation is malignant in some kindreds; hence, despite the
absence of a charge change, minor substitutions in critical regions of
beta-myosin heavy chain protein may also have serious consequences. (4) The
diverse ethnic origins of the two 403Arg-->Gln kindreds provide evidence
suggesting that the identical mutation occurred independently and was
associated with different genetic backgrounds. Their distinct phenotypes
underline the importance of modifying genes and nongenetic factors.
ARTICLES
Genotype-phenotype correlations in hypertrophic cardiomyopathy. Insights provided by comparisons of kindreds with distinct and identical beta-myosin heavy chain gene mutations
Inherited Cardiac Diseases Section, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md. 20892.
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