The p.C759F Variant in USH2A Is a Pathogenic Mutation: Systematic Literature Review and Meta-Analysis of 667 Genotypes

Abstract

Background: Although the p.C759F (c.2276G>T, p.Cys759Phe) variant in the USH2A gene has been identified in association with retinal degeneration by several authors, its pathogenicity has been questioned once by the publication of two unaffected homozygotes from a single family. Objectives: The objective of the study was to ascertain the role of p.C759F in hereditary retinal disease. Methods: We examined 87 research articles reporting on patients carrying this variant and then used this information as primary data for a series of meta-analytical tests. Results: Independent statistical analyses showed that p.C759F (i) is highly enriched in patients with respect to healthy individuals, (ii) represents a clear-cut recessive allele causing disease when it is in trans with other mutations, (iii) is pathogenic in homozygotes. Conclusions: Our results confirm that p.C759F is a bona fide mutation, leading to retinal blindness according to a recessive pattern of inheritance.