Genetic Spectrum of EYS-associated Retinal Disease in a Large Japanese Cohort: Identification of Disease-associated Variants with Relatively High Allele Frequency
Biallelic variants in the EYS gene are a major cause of autosomal recessive inherited retinal disease (IRD), with a high prevalence in the Asian population. The purpose of this study was to identify pathogenic EYS variants, to determine the clinical/genetic spectrum of EYS -associated retinal diseas...
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creator | Yang, Lizhu Fujinami, Kaoru Ueno, Shinji Kuniyoshi, Kazuki Hayashi, Takaaki Kondo, Mineo Mizota, Atsushi Naoi, Nobuhisa Shinoda, Kei Kameya, Shuhei Fujinami-Yokokawa, Yu Liu, Xiao Arno, Gavin Pontikos, Nikolas Kominami, Taro Terasaki, Hiroko Sakuramoto, Hiroyuki Katagiri, Satoshi Mizobuchi, Kei Nakamura, Natsuko Mawatari, Go Kurihara, Toshihide Tsubota, Kazuo Miyake, Yozo Yoshitake, Kazutoshi Iwata, Takeshi Tsunoda, Kazushige |
description | Biallelic variants in the
EYS
gene are a major cause of autosomal recessive inherited retinal disease (IRD), with a high prevalence in the Asian population. The purpose of this study was to identify pathogenic
EYS
variants, to determine the clinical/genetic spectrum of
EYS
-associated retinal disease (
EYS
-RD), and to discover disease-associated variants with relatively high allele frequency (1%-10%) in a nationwide Japanese cohort. Sixty-six affected subjects from 61 families with biallelic or multiple pathogenic/disease-associated
EYS
variants were ascertained by whole-exome sequencing. Three phenotype groups were identified in
EYS
-RD: retinitis pigmentosa (RP; 85.94%), cone-rod dystrophy (CORD; 10.94%), and Leber congenital amaurosis (LCA; 3.12%). Twenty-six pathogenic/disease-associated
EYS
variants were identified, including seven novel variants. The two most prevalent variants, p.(Gly843Glu) and p.(Thr2465Ser) were found in 26 and twelve families (42.6%, 19.7%), respectively, for which the allele frequency (AF) in the Japanese population was 2.2% and 3.0%, respectively. These results expand the phenotypic and genotypic spectrum of
EYS
-RD, accounting for a high proportion of
EYS
-RD both in autosomal recessive RP (23.4%) and autosomal recessive CORD (9.9%) in the Japanese population. The presence of
EYS
variants with relatively high AF highlights the importance of considering the pathogenicity of non-rare variants in relatively prevalent Mendelian disorders. |
doi_str_mv | 10.1038/s41598-020-62119-3 |
format | Article |
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EYS
gene are a major cause of autosomal recessive inherited retinal disease (IRD), with a high prevalence in the Asian population. The purpose of this study was to identify pathogenic
EYS
variants, to determine the clinical/genetic spectrum of
EYS
-associated retinal disease (
EYS
-RD), and to discover disease-associated variants with relatively high allele frequency (1%-10%) in a nationwide Japanese cohort. Sixty-six affected subjects from 61 families with biallelic or multiple pathogenic/disease-associated
EYS
variants were ascertained by whole-exome sequencing. Three phenotype groups were identified in
EYS
-RD: retinitis pigmentosa (RP; 85.94%), cone-rod dystrophy (CORD; 10.94%), and Leber congenital amaurosis (LCA; 3.12%). Twenty-six pathogenic/disease-associated
EYS
variants were identified, including seven novel variants. The two most prevalent variants, p.(Gly843Glu) and p.(Thr2465Ser) were found in 26 and twelve families (42.6%, 19.7%), respectively, for which the allele frequency (AF) in the Japanese population was 2.2% and 3.0%, respectively. These results expand the phenotypic and genotypic spectrum of
EYS
-RD, accounting for a high proportion of
EYS
-RD both in autosomal recessive RP (23.4%) and autosomal recessive CORD (9.9%) in the Japanese population. The presence of
EYS
variants with relatively high AF highlights the importance of considering the pathogenicity of non-rare variants in relatively prevalent Mendelian disorders.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/s41598-020-62119-3</identifier><identifier>PMID: 32218477</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>45/22 ; 45/23 ; 45/41 ; 45/47 ; 631/208/1516/1510 ; 631/208/2489/144 ; Adolescent ; Adult ; Age ; Aged ; Aged, 80 and over ; Alleles ; Asian Continental Ancestry Group - genetics ; Child ; Cohort Studies ; Cone-Rod Dystrophies - genetics ; Congenital diseases ; Dystrophy ; Eye Diseases, Hereditary - genetics ; Eye Proteins - genetics ; Female ; Gene Frequency ; Genes, Recessive ; Genetic Association Studies ; Genetic Variation ; Genotype & phenotype ; Hospitals ; Humanities and Social Sciences ; Humans ; Japan ; Leber congenital amaurosis ; Leber Congenital Amaurosis - genetics ; Male ; Medicine ; Middle Aged ; multidisciplinary ; Mutation ; Pathogenicity ; Pathogens ; Phenotypes ; Population ; Population genetics ; Retina ; Retinal Diseases - genetics ; Retinitis ; Retinitis pigmentosa ; Retinitis Pigmentosa - genetics ; Science ; Science (multidisciplinary) ; Whole Exome Sequencing ; Young Adult</subject><ispartof>Scientific reports, 2020-03, Vol.10 (1), p.5497-5497, Article 5497</ispartof><rights>The Author(s) 2020</rights><rights>This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c522t-dcbd4c6e8e62a368d048c4ef4ee930acf1e3e0325809b1f7d28c1cdaa2a4e0ac3</citedby><cites>FETCH-LOGICAL-c522t-dcbd4c6e8e62a368d048c4ef4ee930acf1e3e0325809b1f7d28c1cdaa2a4e0ac3</cites><orcidid>0000-0002-8874-7111 ; 0000-0002-5457-2720 ; 0000-0001-7787-8194</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7099090/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7099090/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,728,781,785,865,886,27926,27927,41122,42191,51578,53793,53795</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32218477$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yang, Lizhu</creatorcontrib><creatorcontrib>Fujinami, Kaoru</creatorcontrib><creatorcontrib>Ueno, Shinji</creatorcontrib><creatorcontrib>Kuniyoshi, Kazuki</creatorcontrib><creatorcontrib>Hayashi, Takaaki</creatorcontrib><creatorcontrib>Kondo, Mineo</creatorcontrib><creatorcontrib>Mizota, Atsushi</creatorcontrib><creatorcontrib>Naoi, Nobuhisa</creatorcontrib><creatorcontrib>Shinoda, Kei</creatorcontrib><creatorcontrib>Kameya, Shuhei</creatorcontrib><creatorcontrib>Fujinami-Yokokawa, Yu</creatorcontrib><creatorcontrib>Liu, Xiao</creatorcontrib><creatorcontrib>Arno, Gavin</creatorcontrib><creatorcontrib>Pontikos, Nikolas</creatorcontrib><creatorcontrib>Kominami, Taro</creatorcontrib><creatorcontrib>Terasaki, Hiroko</creatorcontrib><creatorcontrib>Sakuramoto, Hiroyuki</creatorcontrib><creatorcontrib>Katagiri, Satoshi</creatorcontrib><creatorcontrib>Mizobuchi, Kei</creatorcontrib><creatorcontrib>Nakamura, Natsuko</creatorcontrib><creatorcontrib>Mawatari, Go</creatorcontrib><creatorcontrib>Kurihara, Toshihide</creatorcontrib><creatorcontrib>Tsubota, Kazuo</creatorcontrib><creatorcontrib>Miyake, Yozo</creatorcontrib><creatorcontrib>Yoshitake, Kazutoshi</creatorcontrib><creatorcontrib>Iwata, Takeshi</creatorcontrib><creatorcontrib>Tsunoda, Kazushige</creatorcontrib><creatorcontrib>JEGC study group</creatorcontrib><creatorcontrib>JEGC study group</creatorcontrib><title>Genetic Spectrum of EYS-associated Retinal Disease in a Large Japanese Cohort: Identification of Disease-associated Variants with Relatively High Allele Frequency</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>Biallelic variants in the
EYS
gene are a major cause of autosomal recessive inherited retinal disease (IRD), with a high prevalence in the Asian population. The purpose of this study was to identify pathogenic
EYS
variants, to determine the clinical/genetic spectrum of
EYS
-associated retinal disease (
EYS
-RD), and to discover disease-associated variants with relatively high allele frequency (1%-10%) in a nationwide Japanese cohort. Sixty-six affected subjects from 61 families with biallelic or multiple pathogenic/disease-associated
EYS
variants were ascertained by whole-exome sequencing. Three phenotype groups were identified in
EYS
-RD: retinitis pigmentosa (RP; 85.94%), cone-rod dystrophy (CORD; 10.94%), and Leber congenital amaurosis (LCA; 3.12%). Twenty-six pathogenic/disease-associated
EYS
variants were identified, including seven novel variants. The two most prevalent variants, p.(Gly843Glu) and p.(Thr2465Ser) were found in 26 and twelve families (42.6%, 19.7%), respectively, for which the allele frequency (AF) in the Japanese population was 2.2% and 3.0%, respectively. These results expand the phenotypic and genotypic spectrum of
EYS
-RD, accounting for a high proportion of
EYS
-RD both in autosomal recessive RP (23.4%) and autosomal recessive CORD (9.9%) in the Japanese population. The presence of
EYS
variants with relatively high AF highlights the importance of considering the pathogenicity of non-rare variants in relatively prevalent Mendelian disorders.</description><subject>45/22</subject><subject>45/23</subject><subject>45/41</subject><subject>45/47</subject><subject>631/208/1516/1510</subject><subject>631/208/2489/144</subject><subject>Adolescent</subject><subject>Adult</subject><subject>Age</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Alleles</subject><subject>Asian Continental Ancestry Group - genetics</subject><subject>Child</subject><subject>Cohort Studies</subject><subject>Cone-Rod Dystrophies - genetics</subject><subject>Congenital diseases</subject><subject>Dystrophy</subject><subject>Eye Diseases, Hereditary - genetics</subject><subject>Eye Proteins - genetics</subject><subject>Female</subject><subject>Gene Frequency</subject><subject>Genes, Recessive</subject><subject>Genetic Association Studies</subject><subject>Genetic Variation</subject><subject>Genotype & phenotype</subject><subject>Hospitals</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Japan</subject><subject>Leber congenital amaurosis</subject><subject>Leber Congenital Amaurosis - genetics</subject><subject>Male</subject><subject>Medicine</subject><subject>Middle Aged</subject><subject>multidisciplinary</subject><subject>Mutation</subject><subject>Pathogenicity</subject><subject>Pathogens</subject><subject>Phenotypes</subject><subject>Population</subject><subject>Population genetics</subject><subject>Retina</subject><subject>Retinal Diseases - genetics</subject><subject>Retinitis</subject><subject>Retinitis pigmentosa</subject><subject>Retinitis Pigmentosa - genetics</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Whole Exome Sequencing</subject><subject>Young Adult</subject><issn>2045-2322</issn><issn>2045-2322</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp9kktvEzEQx1cIRKvSL8ABWeLCZcGvzXo5IFWhLxQJiQISJ2vinU1cOXawvUX5OnxSnCaUwAFfbM385u95VdVzRl8zKtSbJFnTqZpyWk84Y10tHlXHnMqm5oLzxwfvo-o0pVtaTsM7ybqn1VGxMiXb9rj6eYkeszXkZo0mx3FFwkDOv93UkFIwFjL25FMBPDjy3iaEhMR6AmQGcYHkA6zBY7FNwzLE_JZc9-izHayBbIPfiu2jDgW_QrTgcyI_bF4WeVfgO3QbcmUXS3LmHDokFxG_j-jN5ln1ZACX8HR_n1RfLs4_T6_q2cfL6-nZrDYN57nuzbyXZoIKJxzERPVUKiNxkIidoGAGhgKp4I2i3ZwNbc-VYaYH4CCx-MVJ9W6nux7nK-xNKSSC0-toVxA3OoDVf3u8XepFuNMt7Tra0SLwai8QQ0k9Zb2yyaBzpUVhTJoLJXkZgmgL-vIf9DaMsTT5nhKyVazbUnxHmRhSijg8JMOo3m6B3m2BLlug77dAixL04rCMh5DfMy-A2AGpuPwC45-__yP7C91jwOo</recordid><startdate>20200326</startdate><enddate>20200326</enddate><creator>Yang, 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Spectrum of EYS-associated Retinal Disease in a Large Japanese Cohort: Identification of Disease-associated Variants with Relatively High Allele Frequency</title><author>Yang, Lizhu ; Fujinami, Kaoru ; Ueno, Shinji ; Kuniyoshi, Kazuki ; Hayashi, Takaaki ; Kondo, Mineo ; Mizota, Atsushi ; Naoi, Nobuhisa ; Shinoda, Kei ; Kameya, Shuhei ; Fujinami-Yokokawa, Yu ; Liu, Xiao ; Arno, Gavin ; Pontikos, Nikolas ; Kominami, Taro ; Terasaki, Hiroko ; Sakuramoto, Hiroyuki ; Katagiri, Satoshi ; Mizobuchi, Kei ; Nakamura, Natsuko ; Mawatari, Go ; Kurihara, Toshihide ; Tsubota, Kazuo ; Miyake, Yozo ; Yoshitake, Kazutoshi ; Iwata, Takeshi ; Tsunoda, 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Edition)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>ProQuest Science Journals</collection><collection>ProQuest Biological Science Journals</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Scientific reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yang, Lizhu</au><au>Fujinami, Kaoru</au><au>Ueno, Shinji</au><au>Kuniyoshi, Kazuki</au><au>Hayashi, Takaaki</au><au>Kondo, Mineo</au><au>Mizota, Atsushi</au><au>Naoi, Nobuhisa</au><au>Shinoda, Kei</au><au>Kameya, Shuhei</au><au>Fujinami-Yokokawa, Yu</au><au>Liu, Xiao</au><au>Arno, Gavin</au><au>Pontikos, Nikolas</au><au>Kominami, Taro</au><au>Terasaki, Hiroko</au><au>Sakuramoto, Hiroyuki</au><au>Katagiri, Satoshi</au><au>Mizobuchi, Kei</au><au>Nakamura, Natsuko</au><au>Mawatari, Go</au><au>Kurihara, Toshihide</au><au>Tsubota, Kazuo</au><au>Miyake, Yozo</au><au>Yoshitake, Kazutoshi</au><au>Iwata, Takeshi</au><au>Tsunoda, Kazushige</au><aucorp>JEGC study group</aucorp><aucorp>JEGC study group</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Genetic Spectrum of EYS-associated Retinal Disease in a Large Japanese Cohort: Identification of Disease-associated Variants with Relatively High Allele Frequency</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><addtitle>Sci Rep</addtitle><date>2020-03-26</date><risdate>2020</risdate><volume>10</volume><issue>1</issue><spage>5497</spage><epage>5497</epage><pages>5497-5497</pages><artnum>5497</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><abstract>Biallelic variants in the
EYS
gene are a major cause of autosomal recessive inherited retinal disease (IRD), with a high prevalence in the Asian population. The purpose of this study was to identify pathogenic
EYS
variants, to determine the clinical/genetic spectrum of
EYS
-associated retinal disease (
EYS
-RD), and to discover disease-associated variants with relatively high allele frequency (1%-10%) in a nationwide Japanese cohort. Sixty-six affected subjects from 61 families with biallelic or multiple pathogenic/disease-associated
EYS
variants were ascertained by whole-exome sequencing. Three phenotype groups were identified in
EYS
-RD: retinitis pigmentosa (RP; 85.94%), cone-rod dystrophy (CORD; 10.94%), and Leber congenital amaurosis (LCA; 3.12%). Twenty-six pathogenic/disease-associated
EYS
variants were identified, including seven novel variants. The two most prevalent variants, p.(Gly843Glu) and p.(Thr2465Ser) were found in 26 and twelve families (42.6%, 19.7%), respectively, for which the allele frequency (AF) in the Japanese population was 2.2% and 3.0%, respectively. These results expand the phenotypic and genotypic spectrum of
EYS
-RD, accounting for a high proportion of
EYS
-RD both in autosomal recessive RP (23.4%) and autosomal recessive CORD (9.9%) in the Japanese population. The presence of
EYS
variants with relatively high AF highlights the importance of considering the pathogenicity of non-rare variants in relatively prevalent Mendelian disorders.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>32218477</pmid><doi>10.1038/s41598-020-62119-3</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0002-8874-7111</orcidid><orcidid>https://orcid.org/0000-0002-5457-2720</orcidid><orcidid>https://orcid.org/0000-0001-7787-8194</orcidid><oa>free_for_read</oa></addata></record> |
fulltext | fulltext |
identifier | ISSN: 2045-2322 |
ispartof | Scientific reports, 2020-03, Vol.10 (1), p.5497-5497, Article 5497 |
issn | 2045-2322 2045-2322 |
language | eng |
recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7099090 |
source | Springer Open Access; MEDLINE; DOAJ Directory of Open Access Journals; Nature Free; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
subjects | 45/22 45/23 45/41 45/47 631/208/1516/1510 631/208/2489/144 Adolescent Adult Age Aged Aged, 80 and over Alleles Asian Continental Ancestry Group - genetics Child Cohort Studies Cone-Rod Dystrophies - genetics Congenital diseases Dystrophy Eye Diseases, Hereditary - genetics Eye Proteins - genetics Female Gene Frequency Genes, Recessive Genetic Association Studies Genetic Variation Genotype & phenotype Hospitals Humanities and Social Sciences Humans Japan Leber congenital amaurosis Leber Congenital Amaurosis - genetics Male Medicine Middle Aged multidisciplinary Mutation Pathogenicity Pathogens Phenotypes Population Population genetics Retina Retinal Diseases - genetics Retinitis Retinitis pigmentosa Retinitis Pigmentosa - genetics Science Science (multidisciplinary) Whole Exome Sequencing Young Adult |
title | Genetic Spectrum of EYS-associated Retinal Disease in a Large Japanese Cohort: Identification of Disease-associated Variants with Relatively High Allele Frequency |
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