B. Jeschke et al., A HIGH-RISK PHENOTYPE OF HYPERTROPHIC CARDIOMYOPATHY ASSOCIATED WITH A COMPOUND GENOTYPE OF 2 MUTATED BETA-MYOSIN HEAVY-CHAIN GENES, Human genetics, 102(3), 1998, pp. 299-304
Hypertrophic cardiomyopathy (HCM) is a genetically and clinically hete
rogeneous myocardial disease that is in most cases familial and transm
itted in a dominant fashion. The most frequently affected gene codes f
or the cardiac (ventricular) beta-myosin heavy chain. We have investig
ated the genetic cause of an isolated case of HCM, which was marked by
an extremely severe phenotype and a very early age of onset. HCM is n
ormally not a disease of small children. The proband was a boy who had
suffered cardiac arrest at the age of 6.5 years (resuscitation by car
dioconversion). Upon screening of the beta-myosin heavy chain gene as
a candidate, two missense mutations, one in exon 19 (Arg719Trp) and a
second in exon 12 (Met349Thr), were identified. The Arg719Trp mutation
was de novo, as it was not found in the parents. In contrast, the Met
349Thr mutation was inherited through the maternal grandmother. Six fa
mily members were carriers of this mutation but only the proband was c
linically affected. Segregation and molecular analysis allowed us to a
ssign the Met349Thr mutation to the maternal and the Arg719Trp de novo
mutation to the paternal beta-myosin allele. Thus, the patient has no
normal myosin. We interpret these findings in terms of compound heter
ozygosity of a dominant (Arg719Trp) and a recessive (Met349Thr) mutati
on. Whereas a single mutated Arg719Trp allele would be sufficient to c
ause HCM, the concurrent Met349Thr mutation alone does not apparently
induce the disease. Nevertheless, it conceivably contributes to the pa
rticularly severe phenotype.