title: Comprehensive molecular diagnosis of a large cohort of Japanese retinitis pigmentosa and Usher syndrome patients by next-generation sequencing.
abstract: OBJECTIVE
  Retinitis pigmentosa (RP), a major cause of blindness in developed countries, has multiple causative genes; its prevalence differs by ethnicity. Usher syndrome is the most common form of syndromic RP and is accompanied by hearing impairment. Although molecular diagnosis is challenging, recent technological advances such as targeted high-throughput resequencing are efficient screening tools.
  
  
  METHODS
  We performed comprehensive molecular testing in 329 Japanese RP and Usher syndrome patients by using a custom capture panel that covered the coding exons and exon/intron boundaries of all 193 known inherited eye disease genes combined with Illumina HiSequation 2500. Candidate variants were screened using systematic data analyses, and their potential pathogenicity was assessed according to the frequency of the variants in normal populations, in silico prediction tools, and compatibility with known phenotypes or inheritance patterns.
  
  
  RESULTS
  Molecular diagnoses were made in 115/317 RP patients (36.3%) and 6/12 Usher syndrome patients (50%). We identified 104 distinct mutations, including 66 novel mutations. EYS, USH2A, and RHO were common causative genes. In particular, mutations in EYS accounted for 15.0% of the autosomal recessive/simplex RP patients or 10.7% of the entire RP cohort. Among the 189 previously reported mutations detected in the current study, 55 (29.1%) were found commonly in Japanese or other public databases and were excluded from molecular diagnoses.
  
  
  CONCLUSIONS
  By screening a large cohort of patients, this study catalogued the genetic variations involved in RP and Usher syndrome in a Japanese population and highlighted the different distribution of causative genes among populations.
authors.affiliation: Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Maho
authors.initials: M
authors.lastname: Oishi
authors.affiliation: Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Oishi
authors.affiliation: Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Norimoto
authors.initials: N
authors.lastname: Gotoh
authors.affiliation: Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Ogino
authors.affiliation: Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Higasa
authors.affiliation: Medical Research Support Center, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Iida
authors.affiliation: Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Makiyama
authors.affiliation: Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Morooka
authors.affiliation: Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Matsuda
authors.affiliation: Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Nagahisa
authors.initials: N
authors.lastname: Yoshimura
mesh_terms: D004252:DNA Mutational Analysis; D005091:Exons; D016326:Extracellular Matrix Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D005808:Genes, Recessive; D014644:Genetic Variation; D006801:Humans; D007438:Introns; D007564:Japan / Q000453:epidemiology; D008297:Male; D009154:Mutation; D010375:Pedigree; D015995:Prevalence; D012174:Retinitis Pigmentosa / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D012189:Retrospective Studies; D052245:Usher Syndromes / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism
chemical_list: D016326:Extracellular Matrix Proteins
keywords: Usher syndrome; next-generation sequencing; retinitis pigmentosa; targeted resequencing