A Molecular Basis of Familial Hypertrophic Cardiomyopathy 
tion is similar to that associated witli other muta- 
tions, the average age at death is significantly 
older for affected individuals within this family. 
To assess cumulative survival of affected indi- 
viduals with respect to age, we compared sur- 
vival curves of FHC families with five different 
mutations for which sufficient numbers of af- 
fected individuals (alive or deceased) were avail- 
able. These analyses confirmed that persons with 
the Val606Met mutation survive longer than 
those with the Arg453Cys or Arg403Glu 
mutations. 
The Arg249Glu mutation appears to produce 
an intermediate phenotype. Survival in these indi- 
viduals is better than in those with the Arg453Cys 
or the Arg403Glu mutation. While survival ap- 
pears shorter in individuals with the Arg249Glu 
mutation than in those with the Val606Met muta- 
tion, this difference is not statistically significant. 
Individuals with the Arg453Cys mutation (with 
or without the hybrid gene) and those with the 
Arg403Cys mutation have similar life expectan- 
cies, dying prematurely. 
The seven different mutations are clustered in 
the globular head of the polypeptide, and we 
postulate that the defective myosins made by 
these genes poison myosin function by impairing 
physiologic interactions with other contractile el- 
ements. Six of seven missense mutations affect 
the charge of the altered residue. Perhaps the fact 
that the Val606Met mutation does not alter the 
net charge of the polypeptide accounts for the 
better survival of affected individuals. 
Identification of multiple disease-causing mu- 
tations implies that mutational events within the 
iS cardiac MHC gene are not uncommon and that a 
number of FHC-causing cardiac MHC mutations 
have occurred during the course of human evolu- 
tion. A high frequency of myosin mutation may 
explain the relatively high incidence of sporadic 
(10-20 percent) hypertrophic cardiomyopathy. 
The value of identifying FHC mutations was fur- 
ther demonstrated by analysis of a large family 
affected by mutation Arg249Glu. Related adult 
family members were clinically evaluated for 
FHC, and blood samples were obtained for inde- 
pendent genetic diagnosis. The clinical and ge- 
netic diagnoses were in complete concordance. 
Thirteen children (ages 2-20) were also evalu- 
ated. Statistically, half should have been affected, 
but only one child had clinically demonstrable 
FHC. Genotype analysis of these children re- 
vealed six who inherited the mutant MHC gene. 
These data underscored the insensitivity of 
clinical diagnostic criteria for FHC in children 
and young adults. Genetically based diagnoses of 
FHC permit preclinical diagnosis and should fa- 
cilitate prenatal diagnosis. Furthermore, the abil- 
ity to make a preclinical diagnosis in families 
makes possible longitudinal studies of disease de- 
velopment and interventional trials. 
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