Mutations causing familial hypertrophic cardiomyopathy (HCM) have been described in
at least 11 genes encoding cardiac sarcomeric proteins. In this study, three previously
unknown deletions have been identified in the human cardiac genes coding for beta-myosin
heavy chain (MYH7 on chromosome 14) and myosin-binding protein-C (MYBPC3 on chromosome
11). In family MM, a 3-bp deletion in MYH7 was detected to be associated with loss
of glutamic acid in position 927 (DeltaE927) of the myosin rod. In two other families
(HH and NP, related by a common founder) a 2-bp loss in codon 453 (exon 16) of MYBPC3
was identified as the presumable cause of a translation reading frame shift. Taken
together 15 living mutation carriers were investigated. Six deceased family members
(with five cases of premature sudden cardiac death (SCD) in families MM and NP) were
either obligate or suspected mutation carriers. In addition to these mutations a 25-bp
deletion in intron 32 of MYBPC3 was identified in family MM (five carriers) and in
a fourth family (MiR, one HCM patient, three deletion carriers). In agreement with
the loss of the regular splicing branch point in the altered intron 32, a splicing
deficiency was observed in an exon trapping experiment using MYBPC3 exon 33 as a test
substrate. Varying disease profiles assessed using standard clinical, ECG and echocardiographic
procedures in conjunction with mutation analysis led to the following conclusions:
(1) In family MM the DeltaE927 deletion in MYH7 was assumed to be associated with
complete penetrance. Two cases of reported SCD might have been related to this mutation.
(2) The two families, HH and NP, distantly related by a common founder, and both suffering
from a 2-bp deletion in exon 16 of MYBPC3 differed in their average phenotypes. In
family NP, four cases of cardiac death were documented, whereas no cardiac-related
death was reported from family HH. These results support the notion that mutations
in HCM genes may directly determine disease penetrance and severity; however, a contribution
of additional, unidentified factors (genes) to the HCM phenotype can-at least in some
cases-not be excluded. (3) The deletion in intron 32 of MYBPC3 was seen in two families,
but in both its relation to disease was not unequivocal. In addition, this deletion
was observed in 16 of 229 unrelated healthy individuals of the population of the South
Indian states of Kerala and Tamil Nadu. It was not seen in 270 Caucasians from Russia
and western Europe. Hence, it is considered to represent a regional genetic polymorphism
restricted to southern India. The association of the deletion with altered splicing
in transfected cells suggests that this deletion may create a "modifying gene", which
is per se not or only rarely causing HCM, but which may enhance the phenotype of a
mutation responsible for disease.