Genetic investigation and counselling of families with hypertrophic cardiomyopathy.

Editorial Genetic investigation and counselling of families with hypertrophic cardiomyopathy In 1958 Teare described the gross appearances of the heart in eight young people dying suddenly of what became known as hypertrophic cardiomyopathy.' The familial nature of the disease became clear when Teare found himself carrying out a necropsy on a brother of a case in the series. By coincidence on the same day a younger sister attended the Hammersmith Hospital with the clinical signs of hypertrophic cardiomyopathy. Just over 35 years later we are close to understanding the pathogenesis of the disease at the molecular level. Linkage is the classic method of determining the chromosome on which any abnormal gene is situated. This method is better suited to investigating diseases caused by a single gene rather than by several genes. Coinheritance of the disease with another gene or chro-mosomal marker at a known position is compared in affected and unaffected members in two or three generations of a family. Such linkage studies showed a gene causing hypertrophic cardiomyopathy on chromosome 14 in about half of the families in which a member had hypertrophic cardiomyopathy.2 This gene, now known as cardiomyopathy hypertrophic gene 1 (CMH1), encodes for heavy chain myosin, a component of the myofibrillary apparatus of every myocardial muscle cell. Patients with CMH1-related hypertrophic cardiomyopathy are het-erozygous, with one gene encoding for normal myosin and one encoding for the abnormal mutant myosin. Homozygous states are not known, implying that a double dose of the abnormal gene is fatal in utero. This is not quite certain, however, given that both parents would have to be heterozygous and the gene is not common. Thirty four separate point mutations-each the result of a single amino acid substitution-in the gene code for heavy chain myosin have now been reported.3 Most of these so-called missense mutations encode for the head region of the myosin molecule. Occasional families have deletion or rearrangement of a segment of the gene. Such mutations could be expressed as abnormal phenotypes if the abnormal myosin interferes with myofibrillary alignment within the myocyte. This would lead to a misshapen cell and abnormalities of cell to cell alignment. The "disarray" that is such a striking histological feature of hypertrophic cardiomyopathy4 5 iS caused by this malalignment and disorganisation. Current knowledge about the genetics of hypertrophic cardiomyopathy is limited in two important respects. First, if genetic abnormalities of heavy chain myosin account for …