Molecular euphoria.

The genetic location of cystic fibrosis is now known and, by the time you read this, probes sufficiently close for clinical use will have been identified. This is a remarkable international collaborative achievement and is justification for those who, undiscouraged, have persisted with family studies in cystic fibrosis and have incidentally. broken the deadlock of decades. Perhaps at this point we should pause and take stock. In a very few years, many of the major Mendelian disorders have been mapped and, in principle, will be accessible to clinically useful gene probing. The list of mapped disease loci is formidable and includes the haemoglobinopathies, familial hypercholesterolaemia, adult polycystic disease of the kidney, haemophilia A and B, Duchenne muscular dystrophy and other important X linked disorders, Huntington's disease, phenylketonuria, a, antitrypsin deficiency, and others. We now know that only more hard work is needed to complete the human gene map. Already, the power of genetic counselling and prenatal diagnosis have been greatly augmented by the use of gene probes and chorionic villus sampling. The principal technical limitations on the use of probes are those associated with genetically uninformative families. The use of highly heterozygous 'minisatellite' and other hypervariable probes will make more families informative, while closely linked flanking probes will increase accuracy of prediction. When there are no surviving patients, it is likely that linkage disequilibrium will allow some prediction by excluding certain haplotypes found with mutants like a, antitrypsin deficiency. This may not be very specific for most disorders with reasonably high mutation rates, and useful and precise allele specific probes may not be particularly common, judging by the intralocus molecular heterogeneity of many diseases (for example, thalassaemia and phenyl-