DETECTION OF A NEW MUTATION IN THE BETA-MYOSIN HEAVY-CHAIN GENE IN AN INDIVIDUAL WITH HYPERTROPHIC CARDIOMYOPATHY

Familial hypertrophic cardiomyopathy (FHCM) is an autosomal dominant disease affecting primarily the myocardium. The gene responsible for FHCM has been localized to chromosome 14 in some families and several mutations have been described in the beta-myosin heavy chain (betaMHC), a candidate gene for the disease. We recently identified a family with HCM in whom we did not detect any of the known mutations in the betaMHC gene (the alpha/betaMHC hybrid gene and the missense mutation in exons 13 and 9). However, we did observe a novel 9.5-kb BamHI restriction fragment length polymorphism detected by a betaMHC probe on Southern blots of DNA from the proband of this family. Similarly, a novel 3.8-kb TaqI polymorphism and a novel 4.3-kb HindIII polymorphism were detected on Southern blots of DNA from the same proband. Polymerase chain reaction (PCR) was used to amplify the segment of the betaMHC that was detected by pSC14 probe. PCR amplification of the distal 3'-end of the betaMHC gene yielded an additional product in the DNA template from the proband which was subsequently cloned and sequenced. The sequence analysis showed a 2.4-kb nucleotide deletion involving one allele of the betaMHC gene. The deletion includes part of the intron 39, exon 40 including the 3'-untranslated region and the polyadenylation signal, and part of the beta-alphaMHC intergenic region. This deletion was inherited in Mendelian fashion in an additional three members of this small family of which only the proband has developed clinically diagnosed HCM at a very late onset (age 59 yr), the other three family members are younger and have not developed the disease at the ages of 10, 32, and 33 yr.