Improving the diagnosis of cobalamin and related defects by genomic analysis, plus functional and structural assessment of novel variants

[Background] Cellular cobalamin defects are a locus and allelic heterogeneous disorder. The gold standard for coming to genetic diagnoses of cobalamin defects has for some time been gene-by-gene Sanger sequencing of individual DNA fragments. Enzymatic and cellular methods are employed before such se...

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Autores: Brasil, Sandra, Leal, Fátima, Vega, Ana I., Navarrete, Rosa, Ecay, María J., Desviat, Lourdes R., Riera, Casandra, Padilla, Natàlia, de la Cruz, Xavier, Couce, María Luz, Martín-Hernández, Elena, Morais, Ana, Pedrón, Consuelo, Peña-Quintana, Luis, Rigoldi, Miriam, Specola, Norma, de Almeida, Isabel T., Vives, Inmaculada, Yahyaoui, Raquel, Rodríguez-Pombo, Pilar, Ugarte, Magdalena, Pérez-Cerdá, Celia, Merinero, Begoña, Pérez, Belén
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2018
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/168015
Acceso en línea:http://hdl.handle.net/10261/168015
Access Level:acceso abierto
Palabra clave:Cobalamin disorders
Methylmalonic aciduria
Homocystinuria
Massive parallel sequencing
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spelling Improving the diagnosis of cobalamin and related defects by genomic analysis, plus functional and structural assessment of novel variantsBrasil, SandraLeal, FátimaVega, Ana I.Navarrete, RosaEcay, María J.Desviat, Lourdes R.Riera, CasandraPadilla, Natàliade la Cruz, XavierCouce, María LuzMartín-Hernández, ElenaMorais, AnaPedrón, ConsueloPeña-Quintana, LuisRigoldi, MiriamSpecola, Normade Almeida, Isabel T.Vives, InmaculadaYahyaoui, RaquelRodríguez-Pombo, PilarUgarte, MagdalenaPérez-Cerdá, CeliaMerinero, BegoñaPérez, BelénCobalamin disordersMethylmalonic aciduriaHomocystinuriaMassive parallel sequencing[Background] Cellular cobalamin defects are a locus and allelic heterogeneous disorder. The gold standard for coming to genetic diagnoses of cobalamin defects has for some time been gene-by-gene Sanger sequencing of individual DNA fragments. Enzymatic and cellular methods are employed before such sequencing to help in the selection of the gene defects to be sought, but this is time-consuming and laborious. Furthermore some cases remain undiagnosed because no biochemical methods have been available to test for cobalamin absorption and transport defects.[Results] This paper reports the use of massive parallel sequencing of DNA (exome analysis) for the accurate and rapid genetic diagnosis of cobalamin-related defects in a cohort of affected patients. The method was first validated in an initial cohort with different cobalamin defects. Mendelian segregation, the frequency of mutations, and the comprehensive structural and functional analysis of gene variants, identified disease-causing mutations in 12 genes involved in the absorption and synthesis of active cofactors of vitamin B12 (22 cases), and in the non-cobalamin metabolism-related genes ACSF3 (in four biochemically misdiagnosed patients) and SUCLA2 (in one patient with an unusual presentation). We have identified thirteen new variants all classified as pathogenic according to the ACGM recommendation but four were classified as variant likely pathogenic in MUT and SUCLA2. Functional and structural analysis provided evidences to classify them as pathogenic variants.[Conclusions] The present findings suggest that the technology used is sufficiently sensitive and specific, and the results it provides sufficiently reproducible, to recommend its use as a second-tier test after the biochemical detection of cobalamin disorder markers in the first days of life. However, for accurate diagnoses to be made, biochemical and functional tests that allow comprehensive clinical phenotyping are also needed.An institutional grant from the Fundación Ramón Areces to the Centro de Biología Molecular Severo Ochoa, and funding from the European Regional Development Fund, are gratefully acknowledged.This work was funded by grants PI13/01239-PI16/00573; Fundación Isabel Gemio-Fundación La Caixa (LCF/PR/PR16/11110018)Peer reviewedBioMed CentralFundación Ramón ArecesFundación Isabel GemioLa CaixaEuropean Commission2018201820182018info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/168015reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttps://doi.org/10.1186/s13023-018-0862-yinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/1680152026-05-22T06:33:51Z
dc.title.none.fl_str_mv Improving the diagnosis of cobalamin and related defects by genomic analysis, plus functional and structural assessment of novel variants
title Improving the diagnosis of cobalamin and related defects by genomic analysis, plus functional and structural assessment of novel variants
spellingShingle Improving the diagnosis of cobalamin and related defects by genomic analysis, plus functional and structural assessment of novel variants
Brasil, Sandra
Cobalamin disorders
Methylmalonic aciduria
Homocystinuria
Massive parallel sequencing
title_short Improving the diagnosis of cobalamin and related defects by genomic analysis, plus functional and structural assessment of novel variants
title_full Improving the diagnosis of cobalamin and related defects by genomic analysis, plus functional and structural assessment of novel variants
title_fullStr Improving the diagnosis of cobalamin and related defects by genomic analysis, plus functional and structural assessment of novel variants
title_full_unstemmed Improving the diagnosis of cobalamin and related defects by genomic analysis, plus functional and structural assessment of novel variants
title_sort Improving the diagnosis of cobalamin and related defects by genomic analysis, plus functional and structural assessment of novel variants
dc.creator.none.fl_str_mv Brasil, Sandra
Leal, Fátima
Vega, Ana I.
Navarrete, Rosa
Ecay, María J.
Desviat, Lourdes R.
Riera, Casandra
Padilla, Natàlia
de la Cruz, Xavier
Couce, María Luz
Martín-Hernández, Elena
Morais, Ana
Pedrón, Consuelo
Peña-Quintana, Luis
Rigoldi, Miriam
Specola, Norma
de Almeida, Isabel T.
Vives, Inmaculada
Yahyaoui, Raquel
Rodríguez-Pombo, Pilar
Ugarte, Magdalena
Pérez-Cerdá, Celia
Merinero, Begoña
Pérez, Belén
author Brasil, Sandra
author_facet Brasil, Sandra
Leal, Fátima
Vega, Ana I.
Navarrete, Rosa
Ecay, María J.
Desviat, Lourdes R.
Riera, Casandra
Padilla, Natàlia
de la Cruz, Xavier
Couce, María Luz
Martín-Hernández, Elena
Morais, Ana
Pedrón, Consuelo
Peña-Quintana, Luis
Rigoldi, Miriam
Specola, Norma
de Almeida, Isabel T.
Vives, Inmaculada
Yahyaoui, Raquel
Rodríguez-Pombo, Pilar
Ugarte, Magdalena
Pérez-Cerdá, Celia
Merinero, Begoña
Pérez, Belén
author_role author
author2 Leal, Fátima
Vega, Ana I.
Navarrete, Rosa
Ecay, María J.
Desviat, Lourdes R.
Riera, Casandra
Padilla, Natàlia
de la Cruz, Xavier
Couce, María Luz
Martín-Hernández, Elena
Morais, Ana
Pedrón, Consuelo
Peña-Quintana, Luis
Rigoldi, Miriam
Specola, Norma
de Almeida, Isabel T.
Vives, Inmaculada
Yahyaoui, Raquel
Rodríguez-Pombo, Pilar
Ugarte, Magdalena
Pérez-Cerdá, Celia
Merinero, Begoña
Pérez, Belén
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Fundación Ramón Areces
Fundación Isabel Gemio
La Caixa
European Commission
dc.subject.none.fl_str_mv Cobalamin disorders
Methylmalonic aciduria
Homocystinuria
Massive parallel sequencing
topic Cobalamin disorders
Methylmalonic aciduria
Homocystinuria
Massive parallel sequencing
description [Background] Cellular cobalamin defects are a locus and allelic heterogeneous disorder. The gold standard for coming to genetic diagnoses of cobalamin defects has for some time been gene-by-gene Sanger sequencing of individual DNA fragments. Enzymatic and cellular methods are employed before such sequencing to help in the selection of the gene defects to be sought, but this is time-consuming and laborious. Furthermore some cases remain undiagnosed because no biochemical methods have been available to test for cobalamin absorption and transport defects.
publishDate 2018
dc.date.none.fl_str_mv 2018
2018
2018
2018
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/10261/168015
url http://hdl.handle.net/10261/168015
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv https://doi.org/10.1186/s13023-018-0862-y
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
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
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score 15.811543

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