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Comprehensive clinically oriented workflow for nucleotide level resolution and interpretation in prenatal diagnosis of de novo apparently balanced chromosomal translocations in their genomic landscape

2020-04Journal article Restricted access
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dc.contributor.authorDavid, Dezső
dc.contributor.authorFreixo, João P.
dc.contributor.authorFino, Joana
dc.contributor.authorCarvalho, Inês
dc.contributor.authorMarques, Mariana
dc.contributor.authorCardoso, Manuela
dc.contributor.authorPiña-Aguilar, Raul E.
dc.contributor.authorMorton, Cynthia C.
dc.date.accessioned2021-04-07T14:51:56Z
dc.date.available2021-04-07T14:51:56Z
dc.date.issued2020-04
dc.descriptionAcknowledgements We dedicate this article to Maria Guida Boavida who founded the Human Genetics Laboratory as the precursor of the current Department of Human Genetics at the National Health Institute Doutor Ricardo Jorge, Lisbon, Portugal. She and her colleagues performed the first chromosomal prenatal diagnosis from cultured amniocytes in Portugal in July 1977 (no. 77180). However, the first translocation in PND, a paternally inherited Robertsonian t(13;14) (no. 80321), was only identified in June 1980. Almost 40 years later, we report application of an liGS-based approach for the identification of dnBCAs breakpoints in PND. First, we are grateful to the family members for their involvement in this study. We thank Dr. Michael Talkowski and members of his lab for library preparation and sequencing data generation. We thank Jader Cruz for echographic diagnosis of fetal heart defects, to Hildeberto Correia, Ana Cristina Alves and Bárbara Marques for conventional prenatal diagnosis, and to Márcia Rodrigues, Sofia Nunes, Teresa Kay, and Rui Gonçalves for their contribution to the project.pt_PT
dc.description.abstractWe present a comprehensive clinically oriented workflow for large-insert genome sequencing (liGS)-based nucleotide level resolution and interpretation of de novo (dn) apparently balanced chromosomal abnormalities (BCA) in prenatal diagnosis (PND). Retrospective or concomitant with conventional PND and liGS, molecular and newly developed clinically inspired bioinformatic tools (TAD-GConTool and CNV-ConTool) are applied to analyze and assess the functional and phenotypic outcome of dn structural variants (dnSVs). Retrospective analysis of four phenotype-associated dnSVs identified during conventional PND precisely reveal the genomic elements disrupted by the translocation breakpoints. Identification of autosomal dominant disease due to the disruption of ANKS1B and WDR26 by t(12;17)(q23.1;q21.33)dn and t(1;3)(q24.11;p25.3)dn breakpoints, respectively, substantiated the proposed workflow. We then applied this workflow to two ongoing prenatal cases with apparently balanced dnBCAs: 46,XX,t(16;17)(q24;q21.3)dn referred for increased risk on combined first trimester screening and 46,XY,t(2;19)(p13;q13.1)dn referred due to a previous trisomy 21 pregnancy. Translocation breakpoints in the t(16;17) involve ANKRD11 and WNT3 and disruption of ANKRD11 resulted in KBG syndrome confirmed in postnatal follow-up. Breakpoints in the t(2;19) are within ATP6V1B1 and the 3' UTR of CEP89, and are not interpreted to cause disease. Genotype-phenotype correlation confirms the causative role of WDR26 in the Skraban-Deardorff and 1q41q42 microdeletion phenocopy syndromes, and that disruption of ANKS1B causes ANKS1B haploinsufficiency syndrome. In sum, we show that an liGS-based approach can be realized in PND care providing additional information concerning clinical outcomes of dnBCAs in patients with such rearrangements.pt_PT
dc.description.sponsorshipC.C.M. is supported (GM061354) by the National Institutes of Health (USA) and the NIHR Manchester Biomedical Research Centre, UK. This research was supported by national funds through FCT—Fundação para a Ciência e a Tecnologia, Research Grant HMSP-ICT/0016/2013 of the Harvard Medical School—Portugal Program in Translational Research and Informationpt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationHum Genet. 2020 Apr;139(4):531-543. doi: 10.1007/s00439-020-02121-x. Epub 2020 Feb 6.pt_PT
dc.identifier.doi10.1007/s00439-020-02121-xpt_PT
dc.identifier.issn0340-6717
dc.identifier.urihttp://hdl.handle.net/10400.18/7649
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherSpringerpt_PT
dc.relation.publisherversionhttps://link.springer.com/article/10.1007/s00439-020-02121-xpt_PT
dc.subjectAdolescentpt_PT
dc.subjectAdultpt_PT
dc.subjectChromosomes, Humanpt_PT
dc.subjectFemalept_PT
dc.subjectHumanspt_PT
dc.subjectMalept_PT
dc.subjectPregnancypt_PT
dc.subjectWorkflowpt_PT
dc.subjectAbnormalities, Multiplept_PT
dc.subjectBone Diseases, Developmentalpt_PT
dc.subjectChromosome Disorderspt_PT
dc.subjectFaciespt_PT
dc.subjectGenes, Dominantpt_PT
dc.subjectIntellectual Disabilitypt_PT
dc.subjectPrenatal Diagnosispt_PT
dc.subjectTooth Abnormalitiespt_PT
dc.subjectTranslocation, Geneticpt_PT
dc.subjectDoenças Genéticaspt_PT
dc.titleComprehensive clinically oriented workflow for nucleotide level resolution and interpretation in prenatal diagnosis of de novo apparently balanced chromosomal translocations in their genomic landscapept_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/HMSP-ICT%2F0016%2F2013/PT
oaire.citation.endPage543pt_PT
oaire.citation.issue4pt_PT
oaire.citation.startPage531pt_PT
oaire.citation.titleHuman Geneticspt_PT
oaire.citation.volume139pt_PT
oaire.fundingStream3599-PPCDT
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.embargofctAcesso de acordo com política editorial da revista.pt_PT
rcaap.rightsembargoedAccesspt_PT
rcaap.typearticlept_PT
relation.isProjectOfPublication55f3392d-71be-4224-bedd-9feb4a06c428
relation.isProjectOfPublication.latestForDiscovery55f3392d-71be-4224-bedd-9feb4a06c428

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