Ionides, Alexander C. W.; (2002) The clinical and genetic heterogeneity of autosomal dominant cataract. Doctoral thesis (M.D), UCL (University College London).

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Abstract

Aim: The aims of this study are to assess the clinical heterogeneity of autosomal dominant cataract (ADC) between and within different pedigrees and find the loci for genes causing ADC. Methods: Patients with ADC were recruited from the genetic clinic data base at Moorfields Eye Hospital and invited to attend for an eye examination where particular attention was given to the lens, including anterior segment photography. Blood was extracted for DNA analysis and a linkage study undertaken using microsatellite markers. Results: Three hundred and thirty-six individuals were assessed (including members of 16 large pedigrees) and 180 patients found to be affected. In all pedigrees the cataract morphology could be classified as one of the eight following phenotypes; anterior polar, posterior polar, blue-dot (cerulean), lamellar, cortical, nuclear, coralliform and pulverulent. The visual outcomes were found to be related to the phenotypes and the age at time of surgery. Linkage studies identified the gene locus for six pedigrees. A pedigree affected by posterior polar cataract demonstrated linkage to chromosome 1p, a pedigree affected by nuclear cataract to 2q, linkage was also demonstrated for three pedigrees affected by pulverulent cataract, one to 1q and two to 13q and a pedigree affected by anterior polar cataract to 17p. In one of the pedigrees affected by pulverulent cataract a mutation in the connexin50 gene on chromosome 1q was found to give rise to the cataract. Two separate mutations in the gene encoding connexin46 were found to be the cause of the cataract in the two pulverulent pedigrees that demonstrated linkage to 13q. Conclusion: ADC is clinically and genetically heterogeneous. Ten loci have now been shown to contain genes causing ADC and the underlying mutation has been identified in seven genes. There is wide clinical and genetic heterogeneity, but a close correlation exists between the phenotype and the underlying genetic aetiology.

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