Novel Germline Variant in a Patient with Multiple Paragangliomas and Papillary Thyroid Carcinoma.

Over the past few years, next generation technologies have been applied to unravel the genetics of rare inherited diseases, facilitating the discovery of new susceptibility genes. We recently found germline gain-of-function variants in two patients with head and neck paragangliomas causing a charact...

Full description

Bibliographic Details
Authors: Mellid, Sara, Coloma, Javier, Calsina, Bruna, Monteagudo, María, Roldán-Romero, Juan M, Santos, María, Leandro-García, Luis J, Lanillos, Javier, Martínez-Montes, Ángel M, Rodríguez-Antona, Cristina, Montero-Conde, Cristina, Martínez-López, Joaquín, Ayala, Rosa, Matias-Guiu, Xavier, Robledo Batanero, Mercedes, Cascón, Alberto
Format: article
Publication Date:2020
Country:España
Institution:Instituto de Salud Carlos III (ISCIII)
Repository:Repisalud
Language:English
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/26011
Online Access:https://hdl.handle.net/20.500.12105/26011
Access Level:Open access
Keyword:DNMT3A
germline variant
papillary thyroid carcinoma
paraganglioma
id ES_f093ecea2f2159ec277df45e01f4b90e
oai_identifier_str oai:repisalud.isciii.es:20.500.12105/26011
network_acronym_str ES
network_name_str España
repository_id_str
spelling Novel Germline Variant in a Patient with Multiple Paragangliomas and Papillary Thyroid Carcinoma.Mellid, SaraColoma, JavierCalsina, BrunaMonteagudo, MaríaRoldán-Romero, Juan MSantos, MaríaLeandro-García, Luis JLanillos, JavierMartínez-Montes, Ángel MRodríguez-Antona, CristinaMontero-Conde, CristinaMartínez-López, JoaquínAyala, RosaMatias-Guiu, XavierRobledo Batanero, MercedesCascón, AlbertoDNMT3Agermline variantpapillary thyroid carcinomaparagangliomaOver the past few years, next generation technologies have been applied to unravel the genetics of rare inherited diseases, facilitating the discovery of new susceptibility genes. We recently found germline gain-of-function variants in two patients with head and neck paragangliomas causing a characteristic hypermethylated DNA profile. Here, whole-exome sequencing identifies a novel germline variant (p.Gly332Arg) in a patient with bilateral carotid paragangliomas, papillary thyroid carcinoma and idiopathic intellectual disability. The variant, located in the Pro-Trp-Trp-Pro (PWWP) domain of the protein involved in chromatin targeting, affects a residue mutated in papillary thyroid tumors and located between the two residues found mutated in microcephalic dwarfism patients. Structural modelling of the variant in the DNMT3A PWWP domain predicts that the interaction with H3K36me3 will be altered. An increased methylation of target genes, compatible with a gain-of-function effect of the alteration, was observed in saliva DNA from the proband and in one independent acute myeloid leukemia sample carrying the same p.Gly332Arg variant. Although further studies are needed to support a causal role of variants in paraganglioma, the description of a new alteration in a patient with multiple clinical features suggests a heterogeneous phenotypic spectrum related to germline variants.MPDIInstituto de Salud Carlos IIIUnión Europea20252025-01-1320202020-11-0920202020-11-09research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfimage/pngimage/pngimage/pnghttps://hdl.handle.net/20.500.12105/26011reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)InglésengInstituto de Salud Carlos III http://dx.doi.org/10.13039/501100004587 Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016 (ISCIII) PI18%2F00454 CARACTERIZACION MOLECULAR, OMICA Y FUNCIONAL DE MUTACIONES EN EL GEN DLST EN PACIENTES CON FEOCROMOCITOMA%2FPARAGANGLIOMAInstituto de Salud Carlos III http://dx.doi.org/10.13039/501100004587 Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016 (ISCIII) PI17%2F01796 MECANISMOS ASOCIADOS A PROGRESION DE TUMORES ENDOCRINOS Y NEUROENDOCRINOSopen accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/260112026-06-12T12:43:37Z
dc.title.none.fl_str_mv Novel Germline Variant in a Patient with Multiple Paragangliomas and Papillary Thyroid Carcinoma.
title Novel Germline Variant in a Patient with Multiple Paragangliomas and Papillary Thyroid Carcinoma.
spellingShingle Novel Germline Variant in a Patient with Multiple Paragangliomas and Papillary Thyroid Carcinoma.
Mellid, Sara
DNMT3A
germline variant
papillary thyroid carcinoma
paraganglioma
title_short Novel Germline Variant in a Patient with Multiple Paragangliomas and Papillary Thyroid Carcinoma.
title_full Novel Germline Variant in a Patient with Multiple Paragangliomas and Papillary Thyroid Carcinoma.
title_fullStr Novel Germline Variant in a Patient with Multiple Paragangliomas and Papillary Thyroid Carcinoma.
title_full_unstemmed Novel Germline Variant in a Patient with Multiple Paragangliomas and Papillary Thyroid Carcinoma.
title_sort Novel Germline Variant in a Patient with Multiple Paragangliomas and Papillary Thyroid Carcinoma.
dc.creator.none.fl_str_mv Mellid, Sara
Coloma, Javier
Calsina, Bruna
Monteagudo, María
Roldán-Romero, Juan M
Santos, María
Leandro-García, Luis J
Lanillos, Javier
Martínez-Montes, Ángel M
Rodríguez-Antona, Cristina
Montero-Conde, Cristina
Martínez-López, Joaquín
Ayala, Rosa
Matias-Guiu, Xavier
Robledo Batanero, Mercedes
Cascón, Alberto
author Mellid, Sara
author_facet Mellid, Sara
Coloma, Javier
Calsina, Bruna
Monteagudo, María
Roldán-Romero, Juan M
Santos, María
Leandro-García, Luis J
Lanillos, Javier
Martínez-Montes, Ángel M
Rodríguez-Antona, Cristina
Montero-Conde, Cristina
Martínez-López, Joaquín
Ayala, Rosa
Matias-Guiu, Xavier
Robledo Batanero, Mercedes
Cascón, Alberto
author_role author
author2 Coloma, Javier
Calsina, Bruna
Monteagudo, María
Roldán-Romero, Juan M
Santos, María
Leandro-García, Luis J
Lanillos, Javier
Martínez-Montes, Ángel M
Rodríguez-Antona, Cristina
Montero-Conde, Cristina
Martínez-López, Joaquín
Ayala, Rosa
Matias-Guiu, Xavier
Robledo Batanero, Mercedes
Cascón, Alberto
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Instituto de Salud Carlos III
Unión Europea
dc.subject.none.fl_str_mv DNMT3A
germline variant
papillary thyroid carcinoma
paraganglioma
topic DNMT3A
germline variant
papillary thyroid carcinoma
paraganglioma
description Over the past few years, next generation technologies have been applied to unravel the genetics of rare inherited diseases, facilitating the discovery of new susceptibility genes. We recently found germline gain-of-function variants in two patients with head and neck paragangliomas causing a characteristic hypermethylated DNA profile. Here, whole-exome sequencing identifies a novel germline variant (p.Gly332Arg) in a patient with bilateral carotid paragangliomas, papillary thyroid carcinoma and idiopathic intellectual disability. The variant, located in the Pro-Trp-Trp-Pro (PWWP) domain of the protein involved in chromatin targeting, affects a residue mutated in papillary thyroid tumors and located between the two residues found mutated in microcephalic dwarfism patients. Structural modelling of the variant in the DNMT3A PWWP domain predicts that the interaction with H3K36me3 will be altered. An increased methylation of target genes, compatible with a gain-of-function effect of the alteration, was observed in saliva DNA from the proband and in one independent acute myeloid leukemia sample carrying the same p.Gly332Arg variant. Although further studies are needed to support a causal role of variants in paraganglioma, the description of a new alteration in a patient with multiple clinical features suggests a heterogeneous phenotypic spectrum related to germline variants.
publishDate 2020
dc.date.none.fl_str_mv 2020
2020-11-09
2020
2020-11-09
2025
2025-01-13
dc.type.none.fl_str_mv research article
http://purl.org/coar/resource_type/c_2df8fbb1
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://hdl.handle.net/20.500.12105/26011
url https://hdl.handle.net/20.500.12105/26011
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Instituto de Salud Carlos III http://dx.doi.org/10.13039/501100004587 Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016 (ISCIII) PI18%2F00454 CARACTERIZACION MOLECULAR, OMICA Y FUNCIONAL DE MUTACIONES EN EL GEN DLST EN PACIENTES CON FEOCROMOCITOMA%2FPARAGANGLIOMA
Instituto de Salud Carlos III http://dx.doi.org/10.13039/501100004587 Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016 (ISCIII) PI17%2F01796 MECANISMOS ASOCIADOS A PROGRESION DE TUMORES ENDOCRINOS Y NEUROENDOCRINOS
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/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
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
image/png
image/png
image/png
dc.publisher.none.fl_str_mv MPDI
publisher.none.fl_str_mv MPDI
dc.source.none.fl_str_mv reponame:Repisalud
instname:Instituto de Salud Carlos III (ISCIII)
instname_str Instituto de Salud Carlos III (ISCIII)
reponame_str Repisalud
collection Repisalud
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869423969579302912
score 15,812429

Similar Items