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dc.contributor.authorde la Morena-Barrio, Belén
dc.contributor.authorStephens, Jonathan
dc.contributor.authorde la Morena-Barrio, María Eugenia
dc.contributor.authorStefanucci, Luca
dc.contributor.authorPadilla, José
dc.contributor.authorMiñano, Antonia
dc.contributor.authorGleadall, Nicholas
dc.contributor.authorGarcía, Juan Luis
dc.contributor.authorLópez-Fernández, María Fernanda
dc.contributor.authorMorange, Pierre-Emmanuel
dc.contributor.authorPuurunen, Marja
dc.contributor.authorUndas, Anetta
dc.contributor.authorVidal, Francisco
dc.contributor.authorRaymond, Frances Lucy
dc.contributor.authorVicente, Vicente
dc.contributor.authorOuwehand, Willem H
dc.contributor.authorCorral, Javier
dc.contributor.authorSanchis-Juan, Alba
dc.contributor.authorNIHR BioResource
dc.date.accessioned2022-02-03T00:30:55Z
dc.date.available2022-02-03T00:30:55Z
dc.date.issued2022-08
dc.identifier.issn0340-6245
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/333584
dc.description.abstractThe identification of inherited antithrombin deficiency (ATD) is critical to prevent potentially life-threatening thrombotic events. Causal variants in SERPINC1 are identified for up to 70% of cases, the majority being single-nucleotide variants and indels. The detection and characterization of structural variants (SVs) in ATD remain challenging due to the high number of repetitive elements in SERPINC1. Here, we performed long-read whole-genome sequencing on 10 familial and 9 singleton cases with type I ATD proven by functional and antigen assays, who were selected from a cohort of 340 patients with this rare disorder because genetic analyses were either negative, ambiguous, or not fully characterized. We developed an analysis workflow to identify disease-associated SVs. This approach resolved, independently of its size or type, all eight SVs detected by multiple ligation-dependent probe amplification, and identified for the first time a complex rearrangement previously misclassified as a deletion. Remarkably, we identified the mechanism explaining ATD in 2 out of 11 cases with previous unknown defect: the insertion of a novel 2.4 kb SINE-VNTR-Alu retroelement, which was characterized by de novo assembly and verified by specific polymerase chain reaction amplification and sequencing in the probands and affected relatives. The nucleotide-level resolution achieved for all SVs allowed breakpoint analysis, which revealed repetitive elements and microhomologies supporting a common replication-based mechanism for all the SVs. Our study underscores the utility of long-read sequencing technology as a complementary method to identify, characterize, and unveil the molecular mechanism of disease-causing SVs involved in ATD, and enlarges the catalogue of genetic disorders caused by retrotransposon insertions.
dc.description.sponsorshipFunding has also been provided by the National Institute for Health Research England
dc.publisherGeorg Thieme Verlag KG
dc.rightsAll Rights Reserved
dc.rights.urihttp://www.rioxx.net/licenses/all-rights-reserved
dc.titleLong-Read Sequencing Identifies the First Retrotransposon Insertion and Resolves Structural Variants Causing Antithrombin Deficiency.
dc.typeArticle
dc.publisher.departmentDepartment of Haematology
dc.date.updated2022-02-02T15:59:57Z
prism.publicationNameThromb Haemost
dc.identifier.doi10.17863/CAM.81001
dcterms.dateAccepted2022-01-10
rioxxterms.versionofrecord10.1055/s-0042-1749345
rioxxterms.versionAM
dc.contributor.orcidde la Morena-Barrio, Belén [0000-0002-6696-7762]
dc.contributor.orcidde la Morena-Barrio, María Eugenia [0000-0001-7426-4947]
dc.contributor.orcidVidal, Francisco [0000-0001-8089-4945]
dc.identifier.eissn2567-689X
rioxxterms.typeJournal Article/Review
pubs.funder-project-idMedical Research Council (MR/P02002X/1)
pubs.funder-project-idBritish Heart Foundation (RE/18/1/34212)
cam.issuedOnline2022-06-28
cam.orpheus.success2022-02-02 - Embargo set during processing via Fast-track
cam.depositDate2022-02-02
pubs.licence-identifierapollo-deposit-licence-2-1
pubs.licence-display-nameApollo Repository Deposit Licence Agreement
rioxxterms.freetoread.startdate2023-01-10


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