title: Exome sequencing reveals novel and recurrent mutations with clinical significance in inherited retinal dystrophies.
abstract: This study aimed to identify the underlying molecular genetic cause in four Spanish families clinically diagnosed of Retinitis Pigmentosa (RP), comprising one autosomal dominant RP (adRP), two autosomal recessive RP (arRP) and one with two possible modes of inheritance: arRP or X-Linked RP (XLRP). We performed whole exome sequencing (WES) using NimbleGen SeqCap EZ Exome V3 sample preparation kit and SOLID 5500xl platform. All variants passing filter criteria were validated by Sanger sequencing to confirm familial segregation and the absence in local control population. This strategy allowed the detection of: (i) one novel heterozygous splice-site deletion in RHO, c.937-2_944del, (ii) one rare homozygous mutation in C2orf71, c.1795T>C; p.Cys599Arg, not previously associated with the disease, (iii) two heterozygous null mutations in ABCA4, c.2041C>T; p.R681* and c.6088C>T; p.R2030*, and (iv) one mutation, c.2405-2406delAG; p.Glu802Glyfs*31 in the ORF15 of RPGR. The molecular findings for RHO and C2orf71 confirmed the initial diagnosis of adRP and arRP, respectively, while patients with the two ABCA4 mutations, both previously associated with Stargardt disease, presented symptoms of RP with early macular involvement. Finally, the X-Linked inheritance was confirmed for the family with the RPGR mutation. This latter finding allowed the inclusion of carrier sisters in our preimplantational genetic diagnosis program.
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), Seville, Spain.
authors.forename: María
authors.initials: M
authors.lastname: González-del 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), Seville, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Méndez-Vidal
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), Seville, Spain.
authors.forename: Nereida
authors.initials: N
authors.lastname: Bravo-Gil
authors.affiliation: Genomics and Bioinformatics Platform of Andalusia (GBPA), Seville, Spain.
authors.forename: Alicia
authors.initials: A
authors.lastname: Vela-Boza
authors.affiliation: Genomics and Bioinformatics Platform of Andalusia (GBPA), Seville, Spain; Department of Bioinformatics, Prince Felipe Research Centre (CIPF), Valencia, Spain; Functional Genomics Node (INB), Prince Felipe Research Centre (CIPF), Valencia, Spain.
authors.forename: Joaquin
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), Seville, 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), Seville, Spain; Genomics and Bioinformatics Platform of Andalusia (GBPA), Seville, Spain.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Antiñolo
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D020090:Chromosome Segregation / Q000235:genetics; D004252:DNA Mutational Analysis; D059472:Exome / Q000235:genetics*; D005190:Family; D005260:Female; D006801:Humans; D040582:Inheritance Patterns / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D058499:Retinal Dystrophies / Q000235:genetics*; D012243:Rhodopsin / Q000235:genetics
chemical_list: D012243:Rhodopsin