Evans, Kevin; (1994) The molecular genetics of cone-rod retinal dystrophy. Doctoral thesis (M.D.), University of London.

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Abstract

Genetic eye disease is an important and common cause of blindness in the developed World. The choroidoretinal dystrophies make up a significant proportion of this group of conditions. Cone-rod retinal dystrophies are important examples and the term covers a range of phenotypes with common, characteristic electrophysiologic abnormalities. This phenotypic variation may reflect genetic heterogeneity. Working with one large cone-rod dystrophy pedigree, a two part study was undertaken. Initial work was directed at phenotypic characterisation using clinical, electrophysiological and psychophysical techniques. Secondly, a molecular genetic study using the techniques of linkage analysis was undertaken to locate the responsible gene. An early onset, severe, progressive phenotype was identified with central then peripheral areas of cone and rod functional deficit. Macular pigmentary abnormalities with later-onset peripheral intraretinal pigmentation, progressed to extensive chorioretinal atrophy. The phenotype had some features in common with previously described subtypes of cone-rod dystrophy, but differences suggested that clinical subclassifications had not identified different genotypes. Examination of the extended pedigree revealed a segregation distortion superimposed upon the autosomal dominant inheritance pattern. The likelihood of a person being affected was significantly influenced by the sex of the affected parent. This phenomenon, meiotic drive, is rarely observed in man. After exclusion from linkage to known candidate gene loci, multipoint linkage and haplotype analysis localised the cone-rod dystrophy gene to a 5 centimorgan region bounded by genetic markers D19S219 and D19S246. The disease locus is therefore assigned to chromosome 19q13.3-q13.4 and is phenotypically and physically distinct from two other retinal dystrophies (myotonic dystrophy-associated retinopathy and autosomal dominant retinitis pigmentosa) also assigned to this region. Tightly linked flanking markers are now available, sufficient to allow for prenatal diagnosis if requested by family members. Also, the interval containing the disease locus is sufficiently refined to undertake a positional cloning strategy to identify the responsible retinal gene mutation.

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