Genetic Modifiers That Affect Phenotypic Expression of Retinal Diseases

Variability in onset, progression, severity, and phenotypic expression is commonly observed in many retinal diseases (Tables 1 and 2). Although interfamily variability may be caused by environmental or allelic differences, intrafamily variability, when a common mutation is segregating, may also be due to genetic modifiers (1, 2, 3). In contrast to independently acting alleles that may lead to an additive effect on disease severity or age of onset, genetic modifiers are defined as background genes that epistatically interact with a given disease genotype to affect phenotypic outcome. In general, allelic variability at modifier loci does not in itself produce a phenotype. A single gene or possibly a combination of genes in the same or parallel pathways as the mutant gene may act to create a final effect on the expression of the disease phenotype. These modifiers may enhance the effect of the mutation to cause a more severe mutant phenotype or an earlier onset, or conversely, delay or reduce the mutant phenotype even to the extent of completely restoring the wild-type (WT) condition.