A Molecular Basis of Familial Hypertrophic 
Cardiomyopathy 
Jonathan G. Seidman, Ph.D. — Investigator 
Dr. Seidman is also Professor of Genetics at Harvard Medical School. He received his undergraduate degree 
from Harvard University and his Ph.D. degree from the University of Wisconsin-Madison, where he 
studied with William McClain. His postdoctoral studies were carried out in Philip Leder's laboratory at 
the National Institute of Child Health and Human Development. 
FAMILIAL hypertrophic cardiomyopathy (FHC) 
is a heart muscle disorder with an autosomal 
dominant pattern of inheritance. The disease is 
characterized clinically by unexplained myocar- 
dial hypertrophy and variable symptomatology 
that can include syncope, arrhythmias, conges- 
tive heart failure, and sudden death. Diagnosis in 
young people is particularly important. The inci- 
dence of sudden death appears higher in this 
group and can occur without warning. 
Indeed, hypertrophic cardiomyopathy is one of 
the most common autopsy findings among young 
athletes who die suddenly. The large majority of 
these were undiagnosed previously. Diagnosis in 
this age group may be particularly difficult, since 
the diagnostic clinical and echocardiographic cri- 
teria may not be manifest until adulthood. 
Because mutations in the cardiac myosin 
heavy-chain (MHC) genes were implicated as the 
cause of FHC in two families, we decided to un- 
dertake a direct analysis of these genes in affected 
individuals from other families. During the past 
year we spent considerable effort attempting to 
find in 24 unrelated families the cardiac MHC 
mutations that cause FHC. 
We had previously demonstrated that most 
FHC mutations are missense or point mutations in 
the MHC genes. We have successfully employed a 
variety of techniques in the detection of missense 
mutations within genes. Most of these are based 
upon amplification of genomic DNA sequences 
and analyses of individual exons. Application of 
these approaches to the study of FHC mutations 
was more difficult because the ^ MHC polypep- 
tide is encoded in 40 exons, and hence 40 inde- 
pendent analyses are required to examine the en- 
tire gene. Furthermore, FHC is an autosomal 
dominant disorder, and affected individuals are 
heterozygous, bearing one mutated and one nor- 
mal gene. Genomic analyses may fail to detect 
deletions of entire exons or mutations that al- 
tered gene splicing because of the presence of 
one normal gene. 
Access to messenger RNA in which intronic se- 
quences have been excised would overcome 
these limitations and allow analysis of coding re- 
gions in a more rapid and convenient manner. 
Although MHC mRNAs are abundant in the heart, 
expression elsewhere is low and restricted to se- 
lected fibers in slow-twitch skeletal muscle. Nor- 
mal and mutant MHC sequences were detected 
in RNA transcripts from peripheral lympho- 
cytes and lymphocyte cell lines transformed by 
Epstein-Barr virus (EBV) . This finding permitted 
examination of (8 MHC mRNA, even though car- 
diac tissue was not available. 
Seven different ^ cardiac MHC mutations were 
found among 24 unrelated FHC probands. Four 
mutations were identified in two or more fami- 
lies. One of these, the Arg453Cys mutation, prob- 
ably occurred independently in families B and E, 
because only family B also contains a hybrid a/jS 
cardiac MHC gene on the same chromosome. 
Whether other mutations that are shared by appar- 
ently unrelated individuals arose independently 
within mutational hot spots or represent a 
founder mutation is uncertain. Characterization 
of other families should also elucidate whether 
the mutations that can cause the FHC phenotype 
are restricted in number. 
The identification of seven different mutations 
in a disease with significant morbidity and pre- 
mature death suggests that many of these are of 
relatively recent origin in human evolution. 
Since FHC mutations are not likely to provide a 
selective advantage, but have not been lost in the 
population, they probably reflect a high inci- 
dence of new mutational events in the (8 cardiac 
MHC gene. 
The natural history of FHC is quite variable, 
and diagnostic tests have been unable to identify 
those with a more serious prognosis or those at 
risk for sudden, unexpected death. To determine 
whether particular ft cardiac MHC gene muta- 
tions correlate with clinical outcome, we com- 
pared several indices with genotype. Data from 
families with the same mutation are pooled. 
Disease-related deaths were infrequent in fami- 
lies with the Val606Met mutations as compared 
with the Arg249Gln, Arg403Gln, or Arg453Cys 
mutations. While the incidence of disease-related 
deaths in individuals with the Arg249Gln muta- 
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