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

Abstract

<b><i>Background:</i></b> Although the p.C759F (c.2276G&gt;T, p.Cys759Phe) variant in the <i>USH2A</i> 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. <b><i>Objectives:</i></b> The objective of the study was to ascertain the role of p.C759F in hereditary retinal disease. <b><i>Methods:</i></b> 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. <b><i>Results:</i></b> 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 <i>in trans</i> with other mutations, (iii) is pathogenic in homozygotes. <b><i>Conclusions:</i></b> Our results confirm that p.C759F is a bona fide mutation, leading to retinal blindness according to a recessive pattern of inheritance.