Please use this identifier to cite or link to this item: http://hdl.handle.net/10553/49344
DC FieldValueLanguage
dc.contributor.authorBrasil, Sandraen_US
dc.contributor.authorLeal, Fátimaen_US
dc.contributor.authorVega, Anaen_US
dc.contributor.authorNavarrete, Rosaen_US
dc.contributor.authorEcay, María Jesúsen_US
dc.contributor.authorDesviat, Lourdes R.en_US
dc.contributor.authorRiera, Casandraen_US
dc.contributor.authorPadilla, Natàliaen_US
dc.contributor.authorDe La Cruz, Xavieren_US
dc.contributor.authorCouce, Mari Luzen_US
dc.contributor.authorMartin-Hernández, Elenaen_US
dc.contributor.authorMorais, Anaen_US
dc.contributor.authorPedrón, Consueloen_US
dc.contributor.authorPeña-Quintana, Luisen_US
dc.contributor.authorRigoldi, Miriamen_US
dc.contributor.authorSpecola, Normaen_US
dc.contributor.authorDe Almeida, Isabel Tavaresen_US
dc.contributor.authorVives, Inmaculadaen_US
dc.contributor.authorYahyaoui, Raquelen_US
dc.contributor.authorRodríguez-Pombo, Pilaren_US
dc.contributor.authorUgarte, Magdalenaen_US
dc.contributor.authorPérez-Cerda, Celiaen_US
dc.contributor.authorMerinero, Begoñaen_US
dc.contributor.authorPérez, Belénen_US
dc.date.accessioned2018-11-24T06:29:54Z-
dc.date.available2018-11-24T06:29:54Z-
dc.date.issued2018en_US
dc.identifier.issn1750-1172en_US
dc.identifier.otherWoS-
dc.identifier.urihttp://hdl.handle.net/10553/49344-
dc.description.abstractBackground: 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.en_US
dc.languageengen_US
dc.relation.ispartofOrphanet Journal of Rare Diseasesen_US
dc.sourceOrphanet Journal of Rare Diseases [ISSN 1750-1172], v. 13: 125 (Julio 2018)en_US
dc.subject320102 Genética clínicaen_US
dc.subject.otherMethylmalonic Aciduriaen_US
dc.subject.otherInborn Erroren_US
dc.subject.otherVitamin-B-12 Metabolismen_US
dc.subject.otherSequence Variantsen_US
dc.subject.otherB-12 Traffickingen_US
dc.subject.otherMutationsen_US
dc.subject.otherGeneen_US
dc.subject.otherIdentificationen_US
dc.subject.otherDeficiencyen_US
dc.subject.otherStandardsen_US
dc.subject.otherCobalamin Disordersen_US
dc.subject.otherMethylmalonic Aciduriaen_US
dc.subject.otherHomocystinuriaen_US
dc.subject.otherMassive Parallel Sequencingen_US
dc.titleImproving the diagnosis of cobalamin and related defects by genomic analysis, plus functional and structural assessment of novel variantsen_US
dc.typeinfo:eu-repo/semantics/Articleen_US
dc.typeArticleen_US
dc.identifier.doi10.1186/s13023-018-0862-yen_US
dc.identifier.scopus85050856466-
dc.identifier.isi000439706000001-
dc.contributor.authorscopusid49660918100-
dc.contributor.authorscopusid13102658200-
dc.contributor.authorscopusid56226021200-
dc.contributor.authorscopusid14056395300-
dc.contributor.authorscopusid55985505200-
dc.contributor.authorscopusid7003747320-
dc.contributor.authorscopusid55832311300-
dc.contributor.authorscopusid57188676740-
dc.contributor.authorscopusid6603686486-
dc.contributor.authorscopusid7003683107-
dc.contributor.authorscopusid6603425207-
dc.contributor.authorscopusid16316731700-
dc.contributor.authorscopusid57200258861-
dc.contributor.authorscopusid6603266503-
dc.contributor.authorscopusid24559172300-
dc.contributor.authorscopusid6602248369-
dc.contributor.authorscopusid7004144157-
dc.contributor.authorscopusid36998683100-
dc.contributor.authorscopusid24367487400-
dc.contributor.authorscopusid6602708464-
dc.contributor.authorscopusid7005900322-
dc.contributor.authorscopusid6603860348-
dc.contributor.authorscopusid6602854012-
dc.contributor.authorscopusid7101818958-
dc.identifier.issue125-
dc.relation.volume13en_US
dc.investigacionCiencias de la Saluden_US
dc.type2Artículoen_US
dc.contributor.daisngid2479106-
dc.contributor.daisngid34849831-
dc.contributor.daisngid123109-
dc.contributor.daisngid35037979-
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dc.contributor.daisngid9454400-
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dc.contributor.daisngid4394206-
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dc.contributor.daisngid6690714-
dc.contributor.daisngid6795999-
dc.contributor.daisngid1012004-
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dc.contributor.daisngid28222492-
dc.contributor.daisngid593591-
dc.contributor.daisngid5513229-
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dc.contributor.daisngid359367-
dc.contributor.daisngid10326384-
dc.description.numberofpages12en_US
dc.utils.revisionen_US
dc.contributor.wosstandardWOS:Brasil, S-
dc.contributor.wosstandardWOS:Leal, F-
dc.contributor.wosstandardWOS:Vega, A-
dc.contributor.wosstandardWOS:Navarrete, R-
dc.contributor.wosstandardWOS:Ecay, MJ-
dc.contributor.wosstandardWOS:Desviat, LR-
dc.contributor.wosstandardWOS:Riera, C-
dc.contributor.wosstandardWOS:Padilla, N-
dc.contributor.wosstandardWOS:de la Cruz, X-
dc.contributor.wosstandardWOS:Couce, ML-
dc.contributor.wosstandardWOS:Martin-Hernandez, E-
dc.contributor.wosstandardWOS:Morais, A-
dc.contributor.wosstandardWOS:Pedron, C-
dc.contributor.wosstandardWOS:Pena-Quintana, L-
dc.contributor.wosstandardWOS:Rigoldi, M-
dc.contributor.wosstandardWOS:Specola, N-
dc.contributor.wosstandardWOS:de Almeida, IT-
dc.contributor.wosstandardWOS:Vives, I-
dc.contributor.wosstandardWOS:Yahyaoui, R-
dc.contributor.wosstandardWOS:Rodriguez-Pombo, P-
dc.contributor.wosstandardWOS:Ugarte, M-
dc.contributor.wosstandardWOS:Perez-Cerda, C-
dc.contributor.wosstandardWOS:Merinero, B-
dc.contributor.wosstandardWOS:Perez, B-
dc.date.coverdateJulio 2018en_US
dc.identifier.ulpgcen_US
dc.contributor.buulpgcBU-MEDen_US
dc.description.sjr1,589
dc.description.jcr3,687
dc.description.sjrqQ1
dc.description.jcrqQ2
dc.description.scieSCIE
item.fulltextCon texto completo-
item.grantfulltextopen-
crisitem.author.deptGIR IUIBS: Nutrición-
crisitem.author.deptIU de Investigaciones Biomédicas y Sanitarias-
crisitem.author.deptDepartamento de Ciencias Clínicas-
crisitem.author.orcid0000-0001-6052-5894-
crisitem.author.parentorgIU de Investigaciones Biomédicas y Sanitarias-
crisitem.author.fullNamePeña Quintana, Luis-
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