Abstract
Mutations in the peripherin/RDS gene, the BEST1 gene, and the CFH gene appear to be relatively frequent causes of hereditary retinal diseases that principally affect the macula. Intriguingly, a single mutation may be associated with a broad range of retinal phenotypes. Even in a single family, one mutation may show a striking phenotypic variability. Best vitelliform macular dystrophy, caused by mutations in the BEST1 gene, and retinal dystrophies caused by peripherin/RDS gene mutations, are good examples of such variability. This phenotypic variation can only be explained by additional genetic and environmental modifying factors. Conversely, a particular phenotype, such as multifocal vitelliform dystrophy or basal laminar drusen, can be genetically heterogeneous. Despite this variability, distinct genotype-phenotype correlations may be observed in association with specific peripherin/RDS, BEST1, and CFH gene variants. Some phenotypes can be remarkably similar. Multifocal pattern dystrophy simulating Stargardt disease/fundus flavimaculatus, caused by autosomal dominant peripherin/RDS gene mutations, may be confused with autosomal recessive Stargardt disease, which is caused by mutations in the ABCA4 gene. Central areolar choroidal dystrophy, caused by autosomal dominant peripherin/RDS mutations with decreased penetrance, may closely resemble atrophic age-related macular degeneration (AMD). Basal laminar drusen is another phenotype that may be particularly difficult to discern from AMD. This is not surprising, as both conditions are associated with specific variants in the CFH gene. The differential diagnosis of hereditary retinal diseases becomes more difficult in cases of overlapping age at onset and non-penetrance. A combination of well-established but also relatively new imaging techniques such as fundus autofluorescence is useful in the differentiation of these entities. Molecular genetic analysis is able to establish the definitive diagnosis.
