Unmasking Retinitis Pigmentosa complex cases by a whole genome sequencing algorithm based on open‑access tools: hidden recessive inheritance and potential oligogenic variants

Background: Retinitis Pigmentosa (RP) is a clinically and genetically heterogeneous disorder that results in inher‑ ited blindness. Despite the large number of genes identified, only ~ 60% of cases receive a genetic diagnosis using targeted‑sequencing. The aim of this study was to design a whole gen...

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Autores: González‑del Pozo, María, Fernández‑Suárez, Elena, Martín‑Sánchez, Marta, Bravo‑Gil, Nereida, Méndez‑Vidal, Cristina, Rodríguez‑de la Rúa, Enrique, Antiñolo Gil, Guillermo
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2020
País:España
Institución:Universidad de Sevilla (US)
Repositorio:idUS. Depósito de Investigación de la Universidad de Sevilla
OAI Identifier:oai:idus.us.es:11441/156727
Acceso en línea:https://hdl.handle.net/11441/156727
https://doi.org/10.1186/s12967-020-02258-3
Access Level:acceso abierto
Palabra clave:Retinitis Pigmentosa
Inherited retinal dystrophies
WGS
USH2A
ADGRV1
PDZD7
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spelling Unmasking Retinitis Pigmentosa complex cases by a whole genome sequencing algorithm based on open‑access tools: hidden recessive inheritance and potential oligogenic variantsGonzález‑del Pozo, MaríaFernández‑Suárez, ElenaMartín‑Sánchez, MartaBravo‑Gil, NereidaMéndez‑Vidal, CristinaRodríguez‑de la Rúa, EnriqueAntiñolo Gil, GuillermoRetinitis PigmentosaInherited retinal dystrophiesWGSUSH2AADGRV1PDZD7Background: Retinitis Pigmentosa (RP) is a clinically and genetically heterogeneous disorder that results in inher‑ ited blindness. Despite the large number of genes identified, only ~ 60% of cases receive a genetic diagnosis using targeted‑sequencing. The aim of this study was to design a whole genome sequencing (WGS) based approach to increase the diagnostic yield of complex Retinitis Pigmentosa cases. Methods: WGS was conducted in three family members, belonging to one large apparent autosomal dominant RP family that remained unsolved by previous studies, using Illumina TruSeq library preparation kit and Illumina HiSeq X platform. Variant annotation, filtering and prioritization were performed using a number of open‑access tools and public databases. Sanger sequencing of candidate variants was conducted in the extended family members. Results: We have developed and optimized an algorithm, based on the combination of different open‑access tools, for variant prioritization of WGS data which allowed us to reduce significantly the number of likely causative vari‑ ants pending to be manually assessed and segregated. Following this algorithm, four heterozygous variants in one autosomal recessive gene (USH2A) were identified, segregating in pairs in the affected members. Additionally, two pathogenic alleles in ADGRV1 and PDZD7 could be contributing to the phenotype in one patient. Conclusions: The optimization of a diagnostic algorithm for WGS data analysis, accompanied by a hypothesis‑free approach, have allowed us to unmask the genetic cause of the disease in one large RP family, as well as to reassign its inheritance pattern which implies differences in the clinical management of these cases. These results contribute to increasing the number of cases with apparently dominant inheritance that carry causal mutations in recessive genes, as well as the possible involvement of various genes in the pathogenesis of RP in one patient. Moreover, our WGS‑analysis approach, based on open‑access tools, can easily be implemented by other researchers and clinicians to improve the diagnostic yield of additional patients with inherited retinal dystrophies.BMCCirugía2020info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttps://hdl.handle.net/11441/156727https://doi.org/10.1186/s12967-020-02258-3reponame:idUS. Depósito de Investigación de la Universidad de Sevillainstname:Universidad de Sevilla (US)Inglésjournal of Transtational Medicine, 18 (1), 73.https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-020-02258-3info:eu-repo/semantics/openAccessoai:idus.us.es:11441/1567272026-06-17T12:51:07Z
dc.title.none.fl_str_mv Unmasking Retinitis Pigmentosa complex cases by a whole genome sequencing algorithm based on open‑access tools: hidden recessive inheritance and potential oligogenic variants
title Unmasking Retinitis Pigmentosa complex cases by a whole genome sequencing algorithm based on open‑access tools: hidden recessive inheritance and potential oligogenic variants
spellingShingle Unmasking Retinitis Pigmentosa complex cases by a whole genome sequencing algorithm based on open‑access tools: hidden recessive inheritance and potential oligogenic variants
González‑del Pozo, María
Retinitis Pigmentosa
Inherited retinal dystrophies
WGS
USH2A
ADGRV1
PDZD7
title_short Unmasking Retinitis Pigmentosa complex cases by a whole genome sequencing algorithm based on open‑access tools: hidden recessive inheritance and potential oligogenic variants
title_full Unmasking Retinitis Pigmentosa complex cases by a whole genome sequencing algorithm based on open‑access tools: hidden recessive inheritance and potential oligogenic variants
title_fullStr Unmasking Retinitis Pigmentosa complex cases by a whole genome sequencing algorithm based on open‑access tools: hidden recessive inheritance and potential oligogenic variants
title_full_unstemmed Unmasking Retinitis Pigmentosa complex cases by a whole genome sequencing algorithm based on open‑access tools: hidden recessive inheritance and potential oligogenic variants
title_sort Unmasking Retinitis Pigmentosa complex cases by a whole genome sequencing algorithm based on open‑access tools: hidden recessive inheritance and potential oligogenic variants
dc.creator.none.fl_str_mv González‑del Pozo, María
Fernández‑Suárez, Elena
Martín‑Sánchez, Marta
Bravo‑Gil, Nereida
Méndez‑Vidal, Cristina
Rodríguez‑de la Rúa, Enrique
Antiñolo Gil, Guillermo
author González‑del Pozo, María
author_facet González‑del Pozo, María
Fernández‑Suárez, Elena
Martín‑Sánchez, Marta
Bravo‑Gil, Nereida
Méndez‑Vidal, Cristina
Rodríguez‑de la Rúa, Enrique
Antiñolo Gil, Guillermo
author_role author
author2 Fernández‑Suárez, Elena
Martín‑Sánchez, Marta
Bravo‑Gil, Nereida
Méndez‑Vidal, Cristina
Rodríguez‑de la Rúa, Enrique
Antiñolo Gil, Guillermo
author2_role author
author
author
author
author
author
dc.contributor.none.fl_str_mv Cirugía
dc.subject.none.fl_str_mv Retinitis Pigmentosa
Inherited retinal dystrophies
WGS
USH2A
ADGRV1
PDZD7
topic Retinitis Pigmentosa
Inherited retinal dystrophies
WGS
USH2A
ADGRV1
PDZD7
description Background: Retinitis Pigmentosa (RP) is a clinically and genetically heterogeneous disorder that results in inher‑ ited blindness. Despite the large number of genes identified, only ~ 60% of cases receive a genetic diagnosis using targeted‑sequencing. The aim of this study was to design a whole genome sequencing (WGS) based approach to increase the diagnostic yield of complex Retinitis Pigmentosa cases. Methods: WGS was conducted in three family members, belonging to one large apparent autosomal dominant RP family that remained unsolved by previous studies, using Illumina TruSeq library preparation kit and Illumina HiSeq X platform. Variant annotation, filtering and prioritization were performed using a number of open‑access tools and public databases. Sanger sequencing of candidate variants was conducted in the extended family members. Results: We have developed and optimized an algorithm, based on the combination of different open‑access tools, for variant prioritization of WGS data which allowed us to reduce significantly the number of likely causative vari‑ ants pending to be manually assessed and segregated. Following this algorithm, four heterozygous variants in one autosomal recessive gene (USH2A) were identified, segregating in pairs in the affected members. Additionally, two pathogenic alleles in ADGRV1 and PDZD7 could be contributing to the phenotype in one patient. Conclusions: The optimization of a diagnostic algorithm for WGS data analysis, accompanied by a hypothesis‑free approach, have allowed us to unmask the genetic cause of the disease in one large RP family, as well as to reassign its inheritance pattern which implies differences in the clinical management of these cases. These results contribute to increasing the number of cases with apparently dominant inheritance that carry causal mutations in recessive genes, as well as the possible involvement of various genes in the pathogenesis of RP in one patient. Moreover, our WGS‑analysis approach, based on open‑access tools, can easily be implemented by other researchers and clinicians to improve the diagnostic yield of additional patients with inherited retinal dystrophies.
publishDate 2020
dc.date.none.fl_str_mv 2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/11441/156727
https://doi.org/10.1186/s12967-020-02258-3
url https://hdl.handle.net/11441/156727
https://doi.org/10.1186/s12967-020-02258-3
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv journal of Transtational Medicine, 18 (1), 73.
https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-020-02258-3
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv BMC
publisher.none.fl_str_mv BMC
dc.source.none.fl_str_mv reponame:idUS. Depósito de Investigación de la Universidad de Sevilla
instname:Universidad de Sevilla (US)
instname_str Universidad de Sevilla (US)
reponame_str idUS. Depósito de Investigación de la Universidad de Sevilla
collection idUS. Depósito de Investigación de la Universidad de Sevilla
repository.name.fl_str_mv
repository.mail.fl_str_mv
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