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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Veröffentlicht in:Scientific reports 2020-03, Vol.10 (1), p.5497-5497, Article 5497
Hauptverfasser: 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
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container_title Scientific reports
container_volume 10
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
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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. 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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 &amp; 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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</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c522t-dcbd4c6e8e62a368d048c4ef4ee930acf1e3e0325809b1f7d28c1cdaa2a4e0ac3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>45/22</topic><topic>45/23</topic><topic>45/41</topic><topic>45/47</topic><topic>631/208/1516/1510</topic><topic>631/208/2489/144</topic><topic>Adolescent</topic><topic>Adult</topic><topic>Age</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Alleles</topic><topic>Asian Continental Ancestry Group - genetics</topic><topic>Child</topic><topic>Cohort Studies</topic><topic>Cone-Rod Dystrophies - genetics</topic><topic>Congenital diseases</topic><topic>Dystrophy</topic><topic>Eye Diseases, Hereditary - genetics</topic><topic>Eye Proteins - genetics</topic><topic>Female</topic><topic>Gene Frequency</topic><topic>Genes, Recessive</topic><topic>Genetic Association Studies</topic><topic>Genetic Variation</topic><topic>Genotype &amp; phenotype</topic><topic>Hospitals</topic><topic>Humanities and Social Sciences</topic><topic>Humans</topic><topic>Japan</topic><topic>Leber congenital amaurosis</topic><topic>Leber Congenital Amaurosis - genetics</topic><topic>Male</topic><topic>Medicine</topic><topic>Middle Aged</topic><topic>multidisciplinary</topic><topic>Mutation</topic><topic>Pathogenicity</topic><topic>Pathogens</topic><topic>Phenotypes</topic><topic>Population</topic><topic>Population genetics</topic><topic>Retina</topic><topic>Retinal Diseases - genetics</topic><topic>Retinitis</topic><topic>Retinitis pigmentosa</topic><topic>Retinitis Pigmentosa - genetics</topic><topic>Science</topic><topic>Science (multidisciplinary)</topic><topic>Whole Exome Sequencing</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><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><collection>Springer Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>ProQuest Health and Medical</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni 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 &amp; Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health &amp; 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>
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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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