more families. One of these, the Arg453Cys muta- 
tion, probably occurred independently in families B 
and E, because only family B also contains a hybrid 
a//3-cardiac MHC gene on the same chromosome. 
Whether other mutations that are shared between 
apparently unrelated individuals arose indepen- 
dently within mutational hotspots or represent a 
founder mutation is uncertain. 
Characterization of other families should also elu- 
cidate whether there are a restricted number of mu- 
tations that can cause the FHC phenotype. The iden- 
tification of seven different mutations in a disease 
with significant morbidity and premature death sug- 
gests that many of these are new and have appeared 
relatively recently in human evolution. Since FHC 
mutations do not provide a selective advantage, but 
have not been lost in the population, they probably 
reflect a high incidence of new mutational events in 
the |S-cardiac MHC gene. 
This hypothesis was tested by examining the 0- 
MHC mRNA sequences of individuals with sporadic 
hypertrophic cardiomyopathy for missense muta- 
tions. Sporadic hypertrophic cardiomyopathy rather 
than FHC affects 10-30% of individuals with hyper- 
trophic cardiomyopathy. The sporadic form is clini- 
cally indistinguishable from the familial form. How- 
ever, unlike probands with FHC, one of whose 
parents is affected with the disease, neither parent 
of a sporadic hypertrophic cardiomyopathy proband 
is affected. 
Examination of /3-MHC sequences of seven indi- 
viduals with sporadic hypertrophic cardiomyopathy 
revealed two patients with (8-MHC missense muta- 
tions. Neither parent of either patient had the muta- 
tions in their genomes. Apparently new mutations in 
their j8-MHC genes caused the disease in both pro- 
bands. This provides the most convincing evidence 
to date that j8-MHC missense mutations can be re- 
sponsible for hypertrophic cardiomyopathy. Dr. 
Seidman and his colleagues believe that these obser- 
vations will have considerable implications for fu- 
ture diagnosis and treatment of patients with the spo- 
radic form of the disease. 
The natural history of FHC is quite variable, and 
diagnostic tests have been unable to predict those 
with a more serious prognosis — those at risk, for 
example, of sudden, unexpected death. To deter- 
mine whether particular /3-cardiac MHC gene muta- 
tions correlate with clinical outcome, the laboratory 
compared several indices with genotype. Data from 
families with the same mutation are pooled. Dis- 
ease-related deaths were infrequent in families with 
the Val606Met mutations when compared with 
families that have the Arg249Gln, Arg403Gln, or 
Arg453Cys mutations. While the incidence of 
disease-related deaths in individuals with the 
Arg249Gln mutation is similar to that associated 
with other mutations, the average age at death is 
significantly older for affected individuals within 
this family. 
To assess cumulative survival of affected individ- 
uals with respect to age. Dr. Seidman and his col- 
leagues compared survival curves of FHC families 
with five different mutations for which sufficient 
numbers of affected persons (alive or deceased) 
were available. These analyses confirmed that per- 
sons with the Val606Met mutation survive longer 
than those with the Arg453Cys or Arg403Gln muta- 
tions. The Arg249Gln mutation appears to produce 
an intermediate phenotype. Survival with this muta- 
tion is better than with Arg453Cys or Arg403Gln. 
While survival appears shorter in persons with the 
Arg249Gln mutation than in those with the 
Val606Met mutation, the difference is not statisti- 
cally significant. Individuals with the Arg453Cys 
mutation (with or without the hybrid gene) and 
those with the Arg403Gln mutation have similar life 
expectancies, both dying prematurely. 
The value of identifying FHC mutations was fur- 
ther demonstrated by analysis of a large family af- 
fected by mutation Arg249Gln. Related adult family 
members were clinically evaluated for FHC, and 
blood samples were obtained for independent ge- 
netic diagnosis. There was complete concordance 
between the clinical and genetic diagnoses. Thir- 
teen children (ages 2-20) were also evaluated, and 
while statistically half should be affected, only one 
child had clinically demonstrable FHC. Genotype 
analysis of these children revealed 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 diag- 
noses of FHC permit preclinical diagnosis and 
should facilitate prenatal diagnosis. Furthermore, 
the ability to make a preclinical diagnosis in families 
makes possible longitudinal studies of disease devel- 
opment and interventional trials. 
Dr. Seidman is also Professor of Genetics at 
Harvard Medical School. 
Articles 
Chou, Y.-H.W., Brown, E.M., Levi, T., Crowe, G., 
Atkinson, A.B., Arnqvist, H.J., Toss, G., Fuleihan, 
G.E.-H., Seidman, J.G., and Seidman, C.E. 1992. 
The gene responsible for familial hypocalciuric 
hypercalcemia maps to chromosome 3q in four 
unrelated families. Nature Genet 1:295-300. 
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