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SHIGERU SATO, Takeshi Morimoto, Takashi Fujikado, Kohji Nishida; Genetic analysis of inherited retinal degenerative diseases with ｗhole exome sequencing. Invest. Ophthalmol. Vis. Sci. 2018;59(9):5420.
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© ARVO (1962-2015); The Authors (2016-present)
Since inherited retinal degenerative diseases presents genetic heterogeneity, it is difficult to presume the genotype from its phenotype with a few exceptions. This forms big hurdles not only to understand disease pathophysiology but also to do genetic counseling. In this study, we try to identify pathogenic variants in Japanese patients with inherited retinal degenerative diseases.
We conducted an exome sequencing on 52 Japanese patients (25 males and 27 females) with inherited retinal degenerative diseases who visited our clinic and gave a written consent for genetic testing. Syndromic RPs in clinical diagnosis were 4 cases (Usher synd.3, BBS.1). Non syndromic RPs were 38 cases, and 4 cases had family history. 8 cases had macular dystrophy. Other retinal degenerative diseases were 2 cases. For sequencing, Illumina's Hiseq 2500 was used. Sequence data were aligned to the human genome (hg19). Single nucleotide variants (SNVs) and indels were called using GATK and annotated using ANNOVAR. For filtering, we used following condition. 1)The value of ESP (esp6500 siv2 _ all) is <0.01 or no registration. 2)The value of 1000 g (1000 g 2015 aug) is <0.01 or no registration. 3)The value of HGDV (v0.1.9) is <0.01 or no registration. 4)Types of variants are nonsynonymous_SNV, frameshift_deletion, frameshift_insertion, nonframeshift_deletion, nonframeshift_insertion, stoploss, stopgain. 5)Varinatns are contained in the exon region in one of refGene, knownGene, ensGene:(hg19). Furthermore, we narrowed down by the known 764 causative genes registered in Ret.Net.database. The genetic diagnoses were comprehensively determined using various databases (ClinVar, RetNet, dbSNP etc.) and clinical data sets including inherited patterns.
Eleven known pathogenic or likely pathogenic variants which were matched clinical findings were identified. Finally, 17 genetic diagnoses were confirmed. In addition, 19 cases had candidate nonsynonymous variants of uncertain significance. No candidate Variant was detected in 16 cases.
With exome sequences, it was possible to identify causative variants in 33 % of cases. Our result suggest that exome analysis is powerful tool for genetic diagnosis in inherited retinal degenerative diseases. Accumulation of the pathogenicity findings of nonsynonymous variants is expected to further improve the diagnostic rate.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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