دورية أكاديمية
Long-Read Sequencing Identifies the First Retrotransposon Insertion and Resolves Structural Variants Causing Antithrombin Deficiency.
| العنوان: | Long-Read Sequencing Identifies the First Retrotransposon Insertion and Resolves Structural Variants Causing Antithrombin Deficiency. |
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| المؤلفون: | de la Morena-Barrio, Belén, Stephens, Jonathan, de la Morena-Barrio, María Eugenia, Stefanucci, Luca, Padilla, José, Miñano, Antonia, Gleadall, Nicholas, García, Juan Luis, López-Fernández, María Fernanda, Morange, Pierre-Emmanuel, Puurunen, Marja, Undas, Anetta, Vidal, Francisco, Raymond, Frances Lucy, Vicente, Vicente, Ouwehand, Willem H, Corral, Javier, Sanchis-Juan, Alba, NIHR BioResource |
| بيانات النشر: | Georg Thieme Verlag KG Department of Haematology //dx.doi.org/10.1055/s-0042-1749345 Thromb Haemost |
| سنة النشر: | 2022 |
| المجموعة: | Apollo - University of Cambridge Repository |
| مصطلحات موضوعية: | Antithrombin III Deficiency, Antithrombins, Humans, Nucleotides, Retroelements |
| الوصف: | The 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. ; Funding has also been provided by the National Institute for Health Research England |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | English |
| العلاقة: | https://www.repository.cam.ac.uk/handle/1810/333584Test |
| DOI: | 10.17863/CAM.81001 |
| الإتاحة: | https://doi.org/10.17863/CAM.81001Test https://www.repository.cam.ac.uk/handle/1810/333584Test |
| حقوق: | All Rights Reserved ; http://www.rioxx.net/licenses/all-rights-reservedTest |
| رقم الانضمام: | edsbas.4753E0AD |
| قاعدة البيانات: | BASE |
| DOI: | 10.17863/CAM.81001 |
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