Clinical and genetic heterogeneity in autosomal dominant cataract

Aims-To determine the different morphologies of autosomal dominant cataract (ADC), assess the intra- and interfamilial variation in cataract morpholog y, and undertake a genetic linkage study to identify loci for genes causing ADC and detect the underlying mutation. Methods-Patients were recruited fi om the ocular genetic database at Moorfi elds Eye Hospital. All individuals underwent an eye examination with partic ular attention to the lens including anterior segment photography where pos sible. Blood samples were taken for DNA extraction and genetic linkage anal ysis was carried out using polymorphic microsatellite markers. Results-292 individuals from 16 large pedigrees with ADC were examined, of whom 161 were found to be affected. The cataract phenotypes could all be de scribed as one of the eight following morphologies-anterior polar, posterio r polar, nuclear, lamellar, coralliform, blue dot (cerulean), cortical, and pulverulent, The phenotypes varied in severity but the morphology was cons istent within each pedigree, except in those affected by the pulverulent ca taract, which showed considerable intrafamilial variation. Positive linkage was obtained in five families; in two families linkage was demonstrated to new loci and in three families linkage was demonstrated to previously desc ribed loci. In one of the families the underlying mutation was isolated. Ex clusion data were obtained on five families. Conclusion-Although there is considerable clinical heterogeneity in ADC, th e phenotype is usually consistent within families. There is extensive genet ic heterogeneity and specific cataract phenotypes appear to be associated w ith mutations at more than one chromosome locus. In cases where the genetic mutation has been identified the molecular biology and clinical phenotype are closely associated.