Ending diagnostic odyssey by reanalysis of whole exome sequencing data

Initial Whole Exome Sequencing frequently fails to resolve rare disease cases. Bioinformatic reanalysis of existing genomic data utilizes advancing knowledge to enhance diagnosis without additional testing. This study investigated six patients with clinical features consistent with Fanconi Anemia bu...

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Autores: Tejero Laguna, Eudald|||0000-0002-7536-4322, Pujol Calvet, Maria Roser|||0000-0003-1840-5455, Bogliolo, Massimo|||0000-0001-8240-7784, Rodriguez Santiago, Benjamin|||0000-0003-1167-3852, Surralles, Jordi|||0000-0002-4041-7519, Ramírez de Haro, Ma. José|||0000-0003-1417-7731
Tipo de recurso: artículo
Fecha de publicación:2025
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:dnet:uabarcelona_::f1e627e60326b973206b2ff7946989f7
Acceso en línea:https://ddd.uab.cat/record/327747
https://dx.doi.org/urn:doi:10.1186/s13023-025-03928-5
Access Level:acceso abierto
Palabra clave:WES Reanalysis
Rare Genetic Diseases
Fanconi Anemia
Diamond-Blackfan Anemia
Dyskeratosis Congenita
RPL5
TERT
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spelling Ending diagnostic odyssey by reanalysis of whole exome sequencing datareclassification of suspected Fanconi anemia cases to dyskeratosis congenita and Diamond-Blackfan anemiaTejero Laguna, Eudald|||0000-0002-7536-4322Pujol Calvet, Maria Roser|||0000-0003-1840-5455Bogliolo, Massimo|||0000-0001-8240-7784Rodriguez Santiago, Benjamin|||0000-0003-1167-3852Surralles, Jordi|||0000-0002-4041-7519Ramírez de Haro, Ma. José|||0000-0003-1417-7731WES ReanalysisRare Genetic DiseasesFanconi AnemiaDiamond-Blackfan AnemiaDyskeratosis CongenitaRPL5TERTInitial Whole Exome Sequencing frequently fails to resolve rare disease cases. Bioinformatic reanalysis of existing genomic data utilizes advancing knowledge to enhance diagnosis without additional testing. This study investigated six patients with clinical features consistent with Fanconi Anemia but negative chromosomal breakage tests, whose initial genetic analyses were inconclusive. Whole Exome Sequencing data from these patients (collected 2005-2009) underwent comprehensive reanalysis, including single nucleotide variants, insertions/deletions, and copy number variants across genes beyond those typically associated with Fanconi Anemia. Telomere length was assessed via monochrome multiplex quantitative PCR. Reanalysis identified clinically significant variants in two patients (33.3% yield): one harboured a heterozygous pathogenic loss-of-function variant in the Diamond-Blackfan anemia gene RPL5, while the second exhibited compound heterozygous variants in the TERT gene, indicative of dyskeratosis congenita. This study underscores the clinical value of reanalyzing existing genomic data in unresolved suspected genetic disorders, even when phenotype-specific assays are negative. The 33.3% diagnostic yield aligns with gains from larger reanalysis studies (10-25%). Systematic reassessment after sufficient time (24 + months) for genomic advancements offers a cost-effective diagnostic approach for long-undiagnosed cases, highlighting the dynamic nature of genomic interpretation as gene-disease understanding evolves. The online version contains supplementary material available at 10.1186/s13023-025-03928-5. 22025-01-0120252025-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/327747https://dx.doi.org/urn:doi:10.1186/s13023-025-03928-5reponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengAgencia Estatal de Investigación https://doi.org/10.13039/501100011033 PID2021-122411OB-I00Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 PDC2022-133233-I00Agència de Gestió d'Ajuts Universitaris i de Recerca https://doi.org/10.13039/501100003030 2021/SGR-00835open accesshttp://purl.org/coar/access_right/c_abf2Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:dnet:uabarcelona_::f1e627e60326b973206b2ff7946989f72026-06-06T12:50:31Z
dc.title.none.fl_str_mv Ending diagnostic odyssey by reanalysis of whole exome sequencing data
reclassification of suspected Fanconi anemia cases to dyskeratosis congenita and Diamond-Blackfan anemia
title Ending diagnostic odyssey by reanalysis of whole exome sequencing data
spellingShingle Ending diagnostic odyssey by reanalysis of whole exome sequencing data
Tejero Laguna, Eudald|||0000-0002-7536-4322
WES Reanalysis
Rare Genetic Diseases
Fanconi Anemia
Diamond-Blackfan Anemia
Dyskeratosis Congenita
RPL5
TERT
title_short Ending diagnostic odyssey by reanalysis of whole exome sequencing data
title_full Ending diagnostic odyssey by reanalysis of whole exome sequencing data
title_fullStr Ending diagnostic odyssey by reanalysis of whole exome sequencing data
title_full_unstemmed Ending diagnostic odyssey by reanalysis of whole exome sequencing data
title_sort Ending diagnostic odyssey by reanalysis of whole exome sequencing data
dc.creator.none.fl_str_mv Tejero Laguna, Eudald|||0000-0002-7536-4322
Pujol Calvet, Maria Roser|||0000-0003-1840-5455
Bogliolo, Massimo|||0000-0001-8240-7784
Rodriguez Santiago, Benjamin|||0000-0003-1167-3852
Surralles, Jordi|||0000-0002-4041-7519
Ramírez de Haro, Ma. José|||0000-0003-1417-7731
author Tejero Laguna, Eudald|||0000-0002-7536-4322
author_facet Tejero Laguna, Eudald|||0000-0002-7536-4322
Pujol Calvet, Maria Roser|||0000-0003-1840-5455
Bogliolo, Massimo|||0000-0001-8240-7784
Rodriguez Santiago, Benjamin|||0000-0003-1167-3852
Surralles, Jordi|||0000-0002-4041-7519
Ramírez de Haro, Ma. José|||0000-0003-1417-7731
author_role author
author2 Pujol Calvet, Maria Roser|||0000-0003-1840-5455
Bogliolo, Massimo|||0000-0001-8240-7784
Rodriguez Santiago, Benjamin|||0000-0003-1167-3852
Surralles, Jordi|||0000-0002-4041-7519
Ramírez de Haro, Ma. José|||0000-0003-1417-7731
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv WES Reanalysis
Rare Genetic Diseases
Fanconi Anemia
Diamond-Blackfan Anemia
Dyskeratosis Congenita
RPL5
TERT
topic WES Reanalysis
Rare Genetic Diseases
Fanconi Anemia
Diamond-Blackfan Anemia
Dyskeratosis Congenita
RPL5
TERT
description Initial Whole Exome Sequencing frequently fails to resolve rare disease cases. Bioinformatic reanalysis of existing genomic data utilizes advancing knowledge to enhance diagnosis without additional testing. This study investigated six patients with clinical features consistent with Fanconi Anemia but negative chromosomal breakage tests, whose initial genetic analyses were inconclusive. Whole Exome Sequencing data from these patients (collected 2005-2009) underwent comprehensive reanalysis, including single nucleotide variants, insertions/deletions, and copy number variants across genes beyond those typically associated with Fanconi Anemia. Telomere length was assessed via monochrome multiplex quantitative PCR. Reanalysis identified clinically significant variants in two patients (33.3% yield): one harboured a heterozygous pathogenic loss-of-function variant in the Diamond-Blackfan anemia gene RPL5, while the second exhibited compound heterozygous variants in the TERT gene, indicative of dyskeratosis congenita. This study underscores the clinical value of reanalyzing existing genomic data in unresolved suspected genetic disorders, even when phenotype-specific assays are negative. The 33.3% diagnostic yield aligns with gains from larger reanalysis studies (10-25%). Systematic reassessment after sufficient time (24 + months) for genomic advancements offers a cost-effective diagnostic approach for long-undiagnosed cases, highlighting the dynamic nature of genomic interpretation as gene-disease understanding evolves. The online version contains supplementary material available at 10.1186/s13023-025-03928-5.
publishDate 2025
dc.date.none.fl_str_mv 2
2025-01-01
2025
2025-01-01
dc.type.none.fl_str_mv Article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://ddd.uab.cat/record/327747
https://dx.doi.org/urn:doi:10.1186/s13023-025-03928-5
url https://ddd.uab.cat/record/327747
https://dx.doi.org/urn:doi:10.1186/s13023-025-03928-5
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 PID2021-122411OB-I00
Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 PDC2022-133233-I00
Agència de Gestió d'Ajuts Universitaris i de Recerca https://doi.org/10.13039/501100003030 2021/SGR-00835
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Dipòsit Digital de Documents de la UAB
instname:Universitat Autònoma de Barcelona
instname_str Universitat Autònoma de Barcelona
reponame_str Dipòsit Digital de Documents de la UAB
collection Dipòsit Digital de Documents de la UAB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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