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Can the Synergic Contribution of Multigenic Variants Explain the Clinical and Cellular Phenotypes of a Neurodevelopmental Disorder?

2021-12Journal article Open access
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dc.contributor.authorMaia, N
dc.contributor.authorNabais Sá, Maria João
dc.contributor.authorOliveira, Cláudia
dc.contributor.authorSantos, Flávia
dc.contributor.authorSoares, Celia A
dc.contributor.authorPrior, Catarina
dc.contributor.authorTkachenko, Nataliya
dc.contributor.authorSantos, Rosário
dc.contributor.authorde Brouwer, Arjan P. M.
dc.contributor.authorJacome, Ariana
dc.contributor.authorPorto, Beatriz
dc.contributor.authorJorge, Paula
dc.date.accessioned2023-10-24T09:32:38Z
dc.date.available2023-10-24T09:32:38Z
dc.date.issued2021-12
dc.description.abstractWe describe an infant female with a syndromic neurodevelopmental clinical phenotype and increased chromosome instability as cellular phenotype. Genotype characterization revealed heterozygous variants in genes directly or indirectly linked to DNA repair: a de novo X-linked HDAC8 pathogenic variant, a paternally inherited FANCG pathogenic variant and a maternally inherited BRCA2 variant of uncertain significance. The full spectrum of the phenotype cannot be explained by any of the heterozygous variants on their own; thus, a synergic contribution is proposed. Complementation studies showed that the FANCG gene from the Fanconi Anaemia/BRCA (FA/BRCA) DNA repair pathway was impaired, indicating that the variant in FANCG contributes to the cellular phenotype. The patient's chromosome instability represents the first report where heterozygous variant(s) in the FA/BRCA pathway are implicated in the cellular phenotype. We propose that a multigenic contribution of heterozygous variants in HDAC8 and the FA/BRCA pathway might have a role in the phenotype of this neurodevelopmental disorder. The importance of these findings may have repercussion in the clinical management of other cases with a similar synergic contribution of heterozygous variants, allowing the establishment of new genotype-phenotype correlations and motivating the biochemical study of the underlying mechanisms.pt_PT
dc.description.sponsorshipThis work was funded by the European Research Council (ERC) consolidator grant CODECHECK, under the European Union’s Horizon 2020 research and innovation programme (grant agreement 681443). Unit for Multidisciplinary Research in Biomedicine (UMIB) and ITR—Laboratory for Integrative and Translational Research in Population Health, supported by national funds throughthe Foundation for Science and Technology (FCT) Portugal (grant numbers UIDB/00215/2020, UIDP/00215/2020 and LA/P/0064/2020, respectively). N.M. and P.J. were awarded with CHU-Porto grants 2017 DEFI-CHUPorto and 2015 (145/12), respectively. A.J. was granted with the FCT Postdoctoral Fellowship SFRH/BPD/102435/2014 Ref.ª CRM:0012499pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationMaia N, Nabais Sá MJ, Oliveira C, et al. Can the Synergic Contribution of Multigenic Variants Explain the Clinical and Cellular Phenotypes of a Neurodevelopmental Disorder?. Genes (Basel). 2021;13(1):78.doi:10.3390/genes13010078pt_PT
dc.identifier.doi10.3390/genes13010078pt_PT
dc.identifier.issn2073-4425
dc.identifier.urihttp://hdl.handle.net/10400.16/2840
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherMDPIpt_PT
dc.relationUnit for Multidisciplinary Research in Biomedicine
dc.relationLaboratory for Integrative and Translational Research in Population Health
dc.relationDissecting the molecular mechanisms behind the detection and resolution of ultrafine DNA bridges during mitosis – implications for Fanconi Anemia and Bloom Syndrome
dc.relation.publisherversionhttps://www.mdpi.com/2073-4425/13/1/78pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectDNA repair pathwayspt_PT
dc.subjectchromosome instabilitypt_PT
dc.subjectneurodevelopmental disorderpt_PT
dc.titleCan the Synergic Contribution of Multigenic Variants Explain the Clinical and Cellular Phenotypes of a Neurodevelopmental Disorder?pt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleUnit for Multidisciplinary Research in Biomedicine
oaire.awardTitleLaboratory for Integrative and Translational Research in Population Health
oaire.awardTitleDissecting the molecular mechanisms behind the detection and resolution of ultrafine DNA bridges during mitosis – implications for Fanconi Anemia and Bloom Syndrome
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F00215%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/LA%2FP%2F0064%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/FARH/SFRH%2FBPD%2F102435%2F2014/PT
oaire.citation.conferencePlaceSwitzerlandpt_PT
oaire.citation.issue1pt_PT
oaire.citation.startPage78pt_PT
oaire.citation.titleGenespt_PT
oaire.citation.volume13pt_PT
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStreamFARH
person.familyNameMaia
person.familyNameSoares
person.familyNamede Magalhães Claro Prior Pereira Coutinho
person.familyNameSantos
person.familyNameJorge
person.givenNameNuno
person.givenNameCelia Azevedo
person.givenNameAna Catarina
person.givenNameRosário
person.givenNamePaula
person.identifier1058137
person.identifier.ciencia-id4816-1492-FEB1
person.identifier.ciencia-id8014-8739-FEA1
person.identifier.ciencia-idB21D-CC71-AFD0
person.identifier.ciencia-id5717-2E67-9171
person.identifier.ciencia-idFD15-9412-CF3F
person.identifier.orcid0000-0003-3274-2474
person.identifier.orcid0000-0002-2907-0091
person.identifier.orcid0000-0003-4650-264X
person.identifier.orcid0000-0002-8594-6377
person.identifier.orcid0000-0002-6507-222X
person.identifier.ridQ-6511-2016
person.identifier.scopus-author-id57193114189
person.identifier.scopus-author-id57113055700
person.identifier.scopus-author-id7201375082
person.identifier.scopus-author-id7005566496
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
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