GENETIC-HETEROGENEITY AND HOMOG ANALYSIS IN BRITISH MALIGNANT HYPERTHERMIA FAMILIES

Malignant hyperthermia (MH) is an autosomal dominant genetic condition that presents in susceptible people undergoing general anaesthesia. T he clinical disorder is a major cause of anaesthetic morbidity and mor tality. The UK Malignant Hyperthermia Group has performed genetic link age analysis on 20 large, well defined malignant hyperthermia families , using hypervariable markers on chromosome 19q13.1, including the can didate MH gene RYR1, the gene coding for the skeletal muscle ryanodine receptor protein. The results were analysed using LINKAGE to perform two point and multipoint lod scores, then HOMOG to calculate levels of heterogeneity. The results clearly showed genetic heterogeneity betwe en MH families; nine of the families gave results entirely consistent with linkage to the region around RYR1 while the same region was clear ly excluded in three families. In the remaining eight MI-IS families t here were single recombinant events between RYR1 and MH susceptibility . HOMOG analysis was of little added benefit in determining the likeli hood of linkage to RYR1 in these families. This confirmation of the pr esence of heterogeneity in the UK MH population, along with the possib ility of the presence of two MH genes in some pedigrees, indicates tha t it would be premature and potentially dangerous to offer diagnosis o f MH by DNA based methods at this time.