Deep intronic MSH2 variant confirms Muir-Torre subtype of Lynch syndrome

Whole-genome sequencing can uncover clinically significant noncoding variants missed by standard germline testing, as demonstrated in this report in a patient with Muir-Torre syndrome, a subtype of Lynch syndrome. In this case, despite a convincing clinical phenotype and immunohistochemical loss of...

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Detalles Bibliográficos
Autores: Chan Pak Choon, Fiona, Rivera, Barbara, Foulkes, William D.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/226928
Acceso en línea:https://hdl.handle.net/2445/226928
Access Level:acceso abierto
Palabra clave:Epidemiologia genètica
Síndrome de Wolff-Parkinson-White
Metagenòmica
Genetic epidemiology
Wolff-Parkinson-White syndrome
Metagenomics
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spelling Deep intronic MSH2 variant confirms Muir-Torre subtype of Lynch syndromeChan Pak Choon, FionaRivera, BarbaraFoulkes, William D. Epidemiologia genèticaSíndrome de Wolff-Parkinson-WhiteMetagenòmicaGenetic epidemiologyWolff-Parkinson-White syndromeMetagenomicsWhole-genome sequencing can uncover clinically significant noncoding variants missed by standard germline testing, as demonstrated in this report in a patient with Muir-Torre syndrome, a subtype of Lynch syndrome. In this case, despite a convincing clinical phenotype and immunohistochemical loss of MSH2/MSH6 in 1 of the patient's tumors, conventional gene panel testing failed to detect a germline pathogenic variant. Wholegenome sequencing identified a deep intronic MSH2 variant, and tumor sequencing revealed somatic MSH2 mutations (second hits) across multiple tumors, confirming mismatch repair deficiency and establishing a MuirTorre syndrome diagnosis. This report underscores the limitations of routine genetic testing and highlights the clinical utility of whole-genome sequencing in identifying pathogenic variants in noncoding regions. It also emphasizes the role of dermatologists in recognizing cutaneous markers of hereditary cancer syndromes and the importance of interdisciplinary evaluation in guiding both patient care and familial risk assessment.Elsevier BV2025info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/226928Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1016/j.xjidi.2025.100438JID Innovations, 2025, vol. 6, num. 2, 100438https://doi.org/10.1016/j.xjidi.2025.100438cc-by-nc-nd (c) Chan Pak Choon, Fiona et al., 2025https://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/2269282026-05-27T06:46:51Z
dc.title.none.fl_str_mv Deep intronic MSH2 variant confirms Muir-Torre subtype of Lynch syndrome
title Deep intronic MSH2 variant confirms Muir-Torre subtype of Lynch syndrome
spellingShingle Deep intronic MSH2 variant confirms Muir-Torre subtype of Lynch syndrome
Chan Pak Choon, Fiona
Epidemiologia genètica
Síndrome de Wolff-Parkinson-White
Metagenòmica
Genetic epidemiology
Wolff-Parkinson-White syndrome
Metagenomics
title_short Deep intronic MSH2 variant confirms Muir-Torre subtype of Lynch syndrome
title_full Deep intronic MSH2 variant confirms Muir-Torre subtype of Lynch syndrome
title_fullStr Deep intronic MSH2 variant confirms Muir-Torre subtype of Lynch syndrome
title_full_unstemmed Deep intronic MSH2 variant confirms Muir-Torre subtype of Lynch syndrome
title_sort Deep intronic MSH2 variant confirms Muir-Torre subtype of Lynch syndrome
dc.creator.none.fl_str_mv Chan Pak Choon, Fiona
Rivera, Barbara
Foulkes, William D.
author Chan Pak Choon, Fiona
author_facet Chan Pak Choon, Fiona
Rivera, Barbara
Foulkes, William D.
author_role author
author2 Rivera, Barbara
Foulkes, William D.
author2_role author
author
dc.subject.none.fl_str_mv Epidemiologia genètica
Síndrome de Wolff-Parkinson-White
Metagenòmica
Genetic epidemiology
Wolff-Parkinson-White syndrome
Metagenomics
topic Epidemiologia genètica
Síndrome de Wolff-Parkinson-White
Metagenòmica
Genetic epidemiology
Wolff-Parkinson-White syndrome
Metagenomics
description Whole-genome sequencing can uncover clinically significant noncoding variants missed by standard germline testing, as demonstrated in this report in a patient with Muir-Torre syndrome, a subtype of Lynch syndrome. In this case, despite a convincing clinical phenotype and immunohistochemical loss of MSH2/MSH6 in 1 of the patient's tumors, conventional gene panel testing failed to detect a germline pathogenic variant. Wholegenome sequencing identified a deep intronic MSH2 variant, and tumor sequencing revealed somatic MSH2 mutations (second hits) across multiple tumors, confirming mismatch repair deficiency and establishing a MuirTorre syndrome diagnosis. This report underscores the limitations of routine genetic testing and highlights the clinical utility of whole-genome sequencing in identifying pathogenic variants in noncoding regions. It also emphasizes the role of dermatologists in recognizing cutaneous markers of hereditary cancer syndromes and the importance of interdisciplinary evaluation in guiding both patient care and familial risk assessment.
publishDate 2025
dc.date.none.fl_str_mv 2025
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/2445/226928
url https://hdl.handle.net/2445/226928
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1016/j.xjidi.2025.100438
JID Innovations, 2025, vol. 6, num. 2, 100438
https://doi.org/10.1016/j.xjidi.2025.100438
dc.rights.none.fl_str_mv cc-by-nc-nd (c) Chan Pak Choon, Fiona et al., 2025
https://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by-nc-nd (c) Chan Pak Choon, Fiona et al., 2025
https://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier BV
publisher.none.fl_str_mv Elsevier BV
dc.source.none.fl_str_mv Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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