GENOTYPE/PHENOTYPE STUDIES IN HYPERTROPHIC CARDIOMYOPATHY

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Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease. Recently, the betaeta myosin heavy chain (betaMHC) gene has been linked with HCM in about half of the kindreds. We have previously reported that two distinct mutations in the betaMHC gene had markedly different clinical presentations and prognoses: The 908Leu=>Val mutation in a 270 member hypertrophic cardiomyopathy (HCM) kindred was associated with a low incidence of sudden death (SD) and a 61% disease penetrance. The 403Arg=>Gln mutation however, in a 19-member (caucasian) kindred was associated with a high incidence of SD and 100% disease penetrance. Recently, a 606Val=>Met mutation, associated with "near normal survival" in 3 small kindreds has been reported and offered as evidence for the benign nature of neutral charge substitutions. We report 1) a 606Val=>Met kindred with 4 SD occurring in - affected members and 2) a second (oriental) kindred with the 403Arg=>Gln mutation. Although disease was severe and early in both kindreds with the 403Arg=>Gln mutation, cardiac morphology and hemodynamics were distinct. In one kindred all patients had non-obstructive HCM and LV diastolic dysfunction while in the other kindred all patients had obstructive HCM. Thus, 1) large kindreds must be used to judge a mutation benign, 2) 606Val=>Met mutation is malignant in some kindreds and hence minor substitutions in critical regions of betaMHC protein may also have serious consequences, and 3) the diverse ethnic origins of the two 403 kindreds is proof that the identical mutation had occurred independently on two different genetic backgrounds. Their similar yet distinct phenotype underlines the importance of modifying genes.