title: Re-evaluation casts doubt on the pathogenicity of homozygous USH2A p.C759F.
abstract: 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.
authors.affiliation: Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville, University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Spain.
authors.forename: María González-Del
authors.initials: MG
authors.lastname: Pozo
authors.affiliation: Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville, University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Spain.
authors.forename: Nereida
authors.initials: N
authors.lastname: Bravo-Gil
authors.affiliation: Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville, University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Méndez-Vidal
authors.affiliation: Department of Ophthalmology, University Hospital Virgen Macarena, Seville, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Montero-de-Espinosa
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Spain.|Grupo de Investigación en Enfermedades Neurosensoriales, IIS-La Fe, Valencia, Spain.|Unidad de Genética y Diagnóstico Prenatal, Hospital Universitario La Fé, Valencia, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: Millán
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Spain.|Genomics and Bioinformatics Platform of Andalusia (GBPA), Seville, Spain.|Computational Genomics Department, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain.
authors.forename: Joaquín
authors.initials: J
authors.lastname: Dopazo
authors.affiliation: Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville, University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Spain.
authors.forename: Salud
authors.initials: S
authors.lastname: Borrego
authors.affiliation: Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville, University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Spain.|Genomics and Bioinformatics Platform of Andalusia (GBPA), Seville, Spain.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Antiñolo
mesh_terms: D001483:Base Sequence; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000235:genetics*; D016326:Extracellular Matrix Proteins / Q000009:adverse effects / Q000235:genetics*; D015723:Gene Library; D006801:Humans; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics; D010375:Pedigree; D012174:Retinitis Pigmentosa / Q000235:genetics* / Q000473:pathology; D017422:Sequence Analysis, DNA; D013030:Spain
chemical_list: D016326:Extracellular Matrix Proteins; C112735:USH2A protein, human; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; C517431:PDE6B protein, human
keywords: C759F; Usher syndrome; gene panel sequencing; inherited retinal dystrophies; next generation sequencing; rd10; retinitis pigmentosa