Re-evaluation casts doubt on the pathogenicity of homozygous USH2A p.C759F.

TitleRe-evaluation casts doubt on the pathogenicity of homozygous USH2A p.C759F.
Publication TypeJournal Article
Year of Publication2015
AuthorsDel Pozo, MGonzález-, Bravo-Gil, N, Méndez-Vidal, C, Montero-de-Espinosa, I, Millán, JM, Dopazo, J, Borrego, S, Antiňolo, G
JournalAm J Med Genet A
Date Published2015 Jul
KeywordsBase Sequence; Cyclic Nucleotide Phosphodiesterases, Type 6; Extracellular Matrix Proteins; Gene Library; Humans; Molecular Sequence Data; Mutation, Missense; Pedigree; Retinitis pigmentosa; Sequence Analysis, DNA; Spain

Mutations in USH2A are a common cause of Retinitis Pigmentosa (RP). Among the most frequently reported USH2A variants, c.2276G>T (p.C759F) has been found in both affected and healthy individuals. The pathogenicity of this variant remains controversial since it was detected in homozygosity in two healthy siblings of a Spanish family (S23), eleven years ago. The fact that these individuals remain asymptomatic today, prompted us to study the presence of other pathogenic variants in this family using targeted resequencing of 26 retinal genes in one of the affected individuals. This approach allowed us to identify one novel pathogenic homozygous mutation in exon 13 of PDE6B (c.1678C>T; p.R560C). This variant cosegregated with the disease and was absent in 200 control individuals. Remarkably, the identified variant in PDE6B corresponds to the mutation responsible of the retinal degeneration in the naturally occurring rd10 mutant mice. To our knowledge, this is the first report of the identification of the rd10 mice mutation in a RP family. These findings, together with a review of the literature, support the hypothesis that homozygous p.C759F mutations are not pathogenic and led us to exclude the implication of p.C759F in the RP of family S23. Our results indicate the need of re-evaluating all families genetically diagnosed with this mutation.

Alternate JournalAm J Med Genet A
PubMed ID25823529