Long-read sequencing improves the genetic diagnosis of retinitis pigmentosa by identifying an Alu retrotransposon insertion in the EYS gene

[Background] Biallelic variants in EYS are the major cause of autosomal recessive retinitis pigmentosa (arRP) in certain populations, a clinically and genetically heterogeneous disease that may lead to legal blindness. EYS is one of the largest genes (~ 2 Mb) expressed in the retina, in which struct...

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Autores: Fernández-Suárez, Elena, González del Pozo, María, Méndez-Vidal, Cristina, Martín-Sánchez, Marta, Mena, Marcela, Morena-Barrio, Belén de la, Corral, Javier, Borrego, Salud, Antiñolo, Guillermo
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2024
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/388170
Acceso en línea:http://hdl.handle.net/10261/388170
https://api.elsevier.com/content/abstract/scopus_id/85192051925
Access Level:acceso abierto
Palabra clave:Retrotransposon
EYS
Alu insertion
CNV
Inherited retinal diseases
Long-read sequencing
Nanopore sequencing
Retinitis pigmentosa
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network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Long-read sequencing improves the genetic diagnosis of retinitis pigmentosa by identifying an Alu retrotransposon insertion in the EYS gene
title Long-read sequencing improves the genetic diagnosis of retinitis pigmentosa by identifying an Alu retrotransposon insertion in the EYS gene
spellingShingle Long-read sequencing improves the genetic diagnosis of retinitis pigmentosa by identifying an Alu retrotransposon insertion in the EYS gene
Fernández-Suárez, Elena
Retrotransposon
EYS
Alu insertion
CNV
Inherited retinal diseases
Long-read sequencing
Nanopore sequencing
Retinitis pigmentosa
title_short Long-read sequencing improves the genetic diagnosis of retinitis pigmentosa by identifying an Alu retrotransposon insertion in the EYS gene
title_full Long-read sequencing improves the genetic diagnosis of retinitis pigmentosa by identifying an Alu retrotransposon insertion in the EYS gene
title_fullStr Long-read sequencing improves the genetic diagnosis of retinitis pigmentosa by identifying an Alu retrotransposon insertion in the EYS gene
title_full_unstemmed Long-read sequencing improves the genetic diagnosis of retinitis pigmentosa by identifying an Alu retrotransposon insertion in the EYS gene
title_sort Long-read sequencing improves the genetic diagnosis of retinitis pigmentosa by identifying an Alu retrotransposon insertion in the EYS gene
dc.creator.none.fl_str_mv Fernández-Suárez, Elena
González del Pozo, María
Méndez-Vidal, Cristina
Martín-Sánchez, Marta
Mena, Marcela
Morena-Barrio, Belén de la
Corral, Javier
Borrego, Salud
Antiñolo, Guillermo
author Fernández-Suárez, Elena
author_facet Fernández-Suárez, Elena
González del Pozo, María
Méndez-Vidal, Cristina
Martín-Sánchez, Marta
Mena, Marcela
Morena-Barrio, Belén de la
Corral, Javier
Borrego, Salud
Antiñolo, Guillermo
author_role author
author2 González del Pozo, María
Méndez-Vidal, Cristina
Martín-Sánchez, Marta
Mena, Marcela
Morena-Barrio, Belén de la
Corral, Javier
Borrego, Salud
Antiñolo, Guillermo
author2_role author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Junta de Andalucía
Instituto de Salud Carlos III
European Commission
Fundación Cajasol
Fundación Isabel Gemio
Centro de Investigación Biomédica en Red Enfermedades Raras (España)
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Retrotransposon
EYS
Alu insertion
CNV
Inherited retinal diseases
Long-read sequencing
Nanopore sequencing
Retinitis pigmentosa
topic Retrotransposon
EYS
Alu insertion
CNV
Inherited retinal diseases
Long-read sequencing
Nanopore sequencing
Retinitis pigmentosa
description [Background] Biallelic variants in EYS are the major cause of autosomal recessive retinitis pigmentosa (arRP) in certain populations, a clinically and genetically heterogeneous disease that may lead to legal blindness. EYS is one of the largest genes (~ 2 Mb) expressed in the retina, in which structural variants (SVs) represent a common cause of disease. However, their identification using short-read sequencing (SRS) is not always feasible. Here, we conducted targeted long-read sequencing (T-LRS) using adaptive sampling of EYS on the MinION sequencing platform (Oxford Nanopore Technologies) to definitively diagnose an arRP family, whose affected individuals (n = 3) carried the heterozygous pathogenic deletion of exons 32–33 in the EYS gene. As this was a recurrent variant identified in three additional families in our cohort, we also aimed to characterize the known deletion at the nucleotide level to assess a possible founder effect.
publishDate 2024
dc.date.none.fl_str_mv 2024
2025
2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/388170
https://api.elsevier.com/content/abstract/scopus_id/85192051925
url http://hdl.handle.net/10261/388170
https://api.elsevier.com/content/abstract/scopus_id/85192051925
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv The underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.1186/s13100-024-00320-1
https://doi.org/10.1186/s13100-024-00320-1
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv BioMed Central
publisher.none.fl_str_mv BioMed Central
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869411852648185856
spelling Long-read sequencing improves the genetic diagnosis of retinitis pigmentosa by identifying an Alu retrotransposon insertion in the EYS geneFernández-Suárez, ElenaGonzález del Pozo, MaríaMéndez-Vidal, CristinaMartín-Sánchez, MartaMena, MarcelaMorena-Barrio, Belén de laCorral, JavierBorrego, SaludAntiñolo, GuillermoRetrotransposonEYSAlu insertionCNVInherited retinal diseasesLong-read sequencingNanopore sequencingRetinitis pigmentosa[Background] Biallelic variants in EYS are the major cause of autosomal recessive retinitis pigmentosa (arRP) in certain populations, a clinically and genetically heterogeneous disease that may lead to legal blindness. EYS is one of the largest genes (~ 2 Mb) expressed in the retina, in which structural variants (SVs) represent a common cause of disease. However, their identification using short-read sequencing (SRS) is not always feasible. Here, we conducted targeted long-read sequencing (T-LRS) using adaptive sampling of EYS on the MinION sequencing platform (Oxford Nanopore Technologies) to definitively diagnose an arRP family, whose affected individuals (n = 3) carried the heterozygous pathogenic deletion of exons 32–33 in the EYS gene. As this was a recurrent variant identified in three additional families in our cohort, we also aimed to characterize the known deletion at the nucleotide level to assess a possible founder effect.[Results] T-LRS in family A unveiled a heterozygous AluYa5 insertion in the coding exon 43 of EYS (chr6(GRCh37):g.64430524_64430525ins352), which segregated with the disease in compound heterozygosity with the previously identified deletion. Visual inspection of previous SRS alignments using IGV revealed several reads containing soft-clipped bases, accompanied by a slight drop in coverage at the Alu insertion site. This prompted us to develop a simplified program using grep command to investigate the recurrence of this variant in our cohort from SRS data. Moreover, LRS also allowed the characterization of the CNV as a ~ 56.4kb deletion spanning exons 32–33 of EYS (chr6(GRCh37):g.64764235_64820592del). The results of further characterization by Sanger sequencing and linkage analysis in the four families were consistent with a founder variant.[Conclusions] To our knowledge, this is the first report of a mobile element insertion into the coding sequence of EYS, as a likely cause of arRP in a family. Our study highlights the value of LRS technology in characterizing and identifying hidden pathogenic SVs, such as retrotransposon insertions, whose contribution to the etiopathogenesis of rare diseases may be underestimated.This work was supported by the Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Science and Innovation, Spain and co-funded by ERDF (“A way to make Europe”) [PI21-00244]; The strategic plan for the Precision Medicine Infrastructure associated with Science and Technology—IMPaCT [IMP-0009], Regional Ministry of Health and Families of the Autonomous Government of Andalusia [PEER-0501–2019] and the Foundation Isabel Gemio/Foundation Cajasol [FGEMIO-2019–01]. EFS is supported by fellowship FI19/00091 from ISCIII (ESF, “Investing in your future”) and a formative mobility action from CIBERER (ERF02MOV/2023). MMS [RH-0049–2021] is supported by a fellowship funded by the Regional Ministry of Health and Families of the Autonomous Government of Andalusia.Peer reviewedBioMed CentralJunta de AndalucíaInstituto de Salud Carlos IIIEuropean CommissionFundación CajasolFundación Isabel GemioCentro de Investigación Biomédica en Red Enfermedades Raras (España)Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202520252024info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/388170https://api.elsevier.com/content/abstract/scopus_id/85192051925reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)InglésThe underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.1186/s13100-024-00320-1https://doi.org/10.1186/s13100-024-00320-1Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3881702026-05-22T06:33:51Z
score 15,811543

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