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01-07-2018 | Clinical Investigation

Development of a molecular diagnostic test for Retinitis Pigmentosa in the Japanese population

Authors: Akiko Maeda, Akiko Yoshida, Kanako Kawai, Yuki Arai, Ryutaro Akiba, Akira Inaba, Seiji Takagi, Ryoji Fujiki, Yasuhiko Hirami, Yasuo Kurimoto, Osamu Ohara, Masayo Takahashi

Published in: Japanese Journal of Ophthalmology | Issue 4/2018

Abstract

Purpose

Retinitis Pigmentosa (RP) is the most common form of inherited retinal dystrophy caused by different genetic variants. More than 60 causative genes have been identified to date. The establishment of cost-effective molecular diagnostic tests with high sensitivity and specificity can be beneficial for patients and clinicians. Here, we developed a clinical diagnostic test for RP in the Japanese population.

Study design

Evaluation of diagnostic technology, Prospective, Clinical and experimental study.

Methods

A panel of 39 genes reported to cause RP in Japanese patients was established. Next generation sequence (NGS) technology was applied for the analyses of 94 probands with RP and RP-related diseases. After interpretation of detected genetic variants, molecular diagnosis based on a study of the genetic variants and a clinical phenotype was made by a multidisciplinary team including clinicians, researchers and genetic counselors.

Results

NGS analyses found 14,343 variants from 94 probands. Among them, 189 variants in 83 probands (88.3% of all cases) were selected as pathogenic variants and 64 probands (68.1%) have variants which can cause diseases. After the deliberation of these 64 cases, molecular diagnosis was made in 43 probands (45.7%). The final molecular diagnostic rate with the current system combining supplemental Sanger sequencing was 47.9% (45 of 94 cases).

Conclusions

The RP panel provides the significant advantage of detecting genetic variants with a high molecular diagnostic rate. This type of race-specific high-throughput genotyping allows us to conduct a cost-effective and clinically useful genetic diagnostic test.

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den Hollander AI, Black A, Bennett J, Cremers FP. Lighting a candle in the dark: advances in genetics and gene therapy of recessive retinal dystrophies. J Clin Invest. 2010;120:3042–53.CrossRef

Ahuja AK, Dorn JD, Caspi A, McMahon MJ, Dagnelie G, Dacruz L, et al. Blind subjects implanted with the Argus II retinal prosthesis are able to improve performance in a spatial-motor task. Br J Ophthalmol. 2011;95:539–43.CrossRefPubMed

Cheng DL, Greenberg PB, Borton DA. Advances in retinal prosthetic research: a systematic review of engineering and clinical characteristics of current prosthetic initiatives. Curr Eye Res. 2017;42:334–47.CrossRefPubMed

Stone EM, Aldave AJ, Drack AV, Maccumber MW, Sheffield VC, Traboulsi E, et al. Recommendations for genetic testing of inherited eye diseases: report of the American Academy of Ophthalmology task force on genetic testing. Ophthalmology. 2012;119:2408–10.CrossRefPubMed

Neveling K, Collin RW, Gilissen C, van Huet RA, Visser L, Kwint MP, et al. Next-generation genetic testing for retinitis pigmentosa. Hum Mutat. 2012;33:963–72.CrossRefPubMedPubMedCentral

Shanks ME, Downes SM, Copley RR, Lise S, Broxholme J, Hudspith KA, et al. Next-generation sequencing (NGS) as a diagnostic tool for retinal degeneration reveals a much higher detection rate in early-onset disease. Eur J Hum Genet. 2013;21:274–80.CrossRefPubMed

Arai Y, Maeda A, Hirami Y, Ishigami C, Kosugi S, Mandai M, et al. Retinitis pigmentosa with EYS mutations is the most prevalent inherited retinal dystrophy in Japanese populations. J Ophthalmol. 2015;2015:819760.CrossRefPubMedPubMedCentral

Oishi M, Oishi A, Gotoh N, Ogino K, Higasa K, Iida K, et al. Comprehensive molecular diagnosis of a large cohort of Japanese retinitis pigmentosa and Usher syndrome patients by next-generation sequencing. Invest Ophthalmol Vis Sci. 2014;55:7369–75.CrossRefPubMed

Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucl Acids Res. 2010;38:e164.CrossRefPubMedPubMedCentral

10.

Higasa K, Miyake N, Yoshimura J, Okamura K, Niihori T, Saitsu H, et al. Human genetic variation database, a reference database of genetic variations in the Japanese population. J Hum Genet. 2016;61:547–53.CrossRefPubMedPubMedCentral

11.

Narahara M, Higasa K, Nakamura S, Tabara Y, Kawaguchi T, Ishii M, et al. Large-scale East-Asian eQTL mapping reveals novel candidate genes for LD mapping and the genomic landscape of transcriptional effects of sequence variants. PLoS ONE. 2014;9:e100924.CrossRefPubMedPubMedCentral

12.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24.CrossRefPubMedPubMedCentral

13.

Dryja TP, McGee TL, Hahn LB, Cowley GS, Olsson JE, Reichel E, et al. Mutations within the rhodopsin gene in patients with autosomal dominant retinitis pigmentosa. N Engl J Med. 1990;323:1302–7.CrossRefPubMed

14.

Daiger SP, Shankar SP, Schindler AB, Sullivan LS, Bowne SJ, King TM, et al. Genetic factors modifying clinical expression of autosomal dominant RP. Adv Exp Med Biol. 2006;572:3–8.CrossRefPubMedPubMedCentral

15.

Zhao Y, Hosono K, Suto K, Ishigami C, Arai Y, Hikoya A, et al. The first USH2A mutation analysis of Japanese autosomal recessive retinitis pigmentosa patients: a totally different mutation profile with the lack of frequent mutations found in Caucasian patients. J Hum Genet. 2014;59:521–8.CrossRefPubMed

16.

Hosono K, Ishigami C, Takahashi M, Park DH, Hirami Y, Nakanishi H, et al. Two novel mutations in the EYS gene are possible major causes of autosomal recessive retinitis pigmentosa in the Japanese population. PLoS ONE. 2012;7:e31036.CrossRefPubMedPubMedCentral

17.

Li Q, Wang K. InterVar: clinical interpretation of genetic variants by the 2015 ACMG-AMP guidelines. Am J Hum Genet. 2017;100:267–80.CrossRefPubMedPubMedCentral

18.

Sullivan LS, Bowne SJ, Birch DG, Hughbanks-Wheaton D, Heckenlively JR, Lewis RA, et al. Prevalence of disease-causing mutations in families with autosomal dominant retinitis pigmentosa: a screen of known genes in 200 families. Invest Ophthalmol Vis Sci. 2006;47:3052–64.CrossRefPubMedPubMedCentral

19.

Seyedahmadi BJ, Rivolta C, Keene JA, Berson EL, Dryja TP. Comprehensive screening of the USH2A gene in Usher syndrome type II and non-syndromic recessive retinitis pigmentosa. Exp Eye Res. 2004;79:167–73.CrossRefPubMed

20.

Iwanami M, Oshikawa M, Nishida T, Nakadomari S, Kato S. High prevalence of mutations in the EYS gene in Japanese patients with autosomal recessive retinitis pigmentosa. Invest Ophthalmol Vis Sci. 2012;53:1033–40.CrossRefPubMed

21.

Miyake M, Yamashiro K, Tamura H, Kumagai K, Saito M, Sugahara-Kuroda M, et al. The contribution of genetic architecture to the 10-year incidence of age-related macular degeneration in the fellow eye. Invest Ophthalmol Vis Sci. 2015;56:5353–61.CrossRefPubMed

22.

Akahori M, Tsunoda K, Miyake Y, Fukuda Y, Ishiura H, Tsuji S, et al. Dominant mutations in RP1L1 are responsible for occult macular dystrophy. Am J Hum Genet. 2010;87:424–9.CrossRefPubMedPubMedCentral

23.

Li A, Jiao X, Munier FL, Schorderet DF, Yao W, Iwata F, et al. Bietti crystalline corneoretinal dystrophy is caused by mutations in the novel gene CYP4V2. Am J Hum Genet. 2004;74:817–26.CrossRefPubMedPubMedCentral

24.

Lin J, Nishiguchi KM, Nakamura M, Dryja TP, Berson EL, Miyake Y. Recessive mutations in the CYP4V2 gene in East Asian and Middle Eastern patients with Bietti crystalline corneoretinal dystrophy. J Med Genet. 2005;42:e38.CrossRefPubMedPubMedCentral

Title: Development of a molecular diagnostic test for Retinitis Pigmentosa in the Japanese population
Authors: Akiko Maeda
Akiko Yoshida
Kanako Kawai
Yuki Arai
Ryutaro Akiba
Akira Inaba
Seiji Takagi
Ryoji Fujiki
Yasuhiko Hirami
Yasuo Kurimoto
Osamu Ohara
Masayo Takahashi
Publication date: 01-07-2018
Publisher: Springer Japan
Published in: Japanese Journal of Ophthalmology / Issue 4/2018
Print ISSN: 0021-5155
Electronic ISSN: 1613-2246
DOI: https://doi.org/10.1007/s10384-018-0601-x

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Development of a molecular diagnostic test for Retinitis Pigmentosa in the Japanese population

Abstract

Purpose

Study design

Methods

Results

Conclusions

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Purpose

Study design

Methods

Results

Conclusions

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