Rapid Genetic Screen for Common β-Myosin Heavy Chain Mutations Causing Familial Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM), an autosomal dominant disease and the most common cause of sudden death in the young, is diagnosed by echocardiographic detection of cardiac hypertrophy. Unfortunately, the hypertrophy is usually not detectable until adolescence, which may be too late since sudden death often occurs as the first symptom. The availability of clinical genetic assay to detect mutations would provide definitive diagnosis, independent of clinical features and can be made at or before birth. Computer analysis showed most of the known mutations in the βMHC gene involve restriction enzyme recognition site which can be exploited as rapid genetic screening test. Accordingly, we employed polymerase chain reaction (PCR) to amplify the involved region of the gene followed by enzyme restriction digestion for 15 known mutations in 122 families with HCM. Fourteen families were positive and 108 negative. Ten families carried one of the three mutations known to have high incidence of sudden death with 26 offspring having the mutation and at risk for sudden death while 49 did not have the mutation and are not at risk of developing HCM. Four families had one of the three known benign mutations with 23 offspring having the mutation and 21 without. The mutations were confirmed by sequencing and shown to be co-inherited with the disease. This test provides for definitive genetic diagnosis and identifies those with the mutation and at risk for HCM and those without who will not develop HCM. Genetic counseling can be given prior to development of symptoms and those with mutations having high incidence of sudden death are candidates for electrophysiology testing and possible implantation of cardiac defibrillators or amiodarone therapy. The test requires only blood sample, is simple to perform and results are available in 48 hours. Over 25 of the βMHC mutations have now been shown to be amenable to rapid genetic diagnosis using PCR and restriction enzyme digestion.