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Long-read sequencing resolves structural variants in SERPINC1 causing antithrombin deficiency and identifies a complex rearrangement and a retrotransposon insertion not characterized by routine diagnostic methods

Publication

Date: 28th August 2020 | Source: bioRxiv

Authors: Belén de la Morena-Barrio, Jonathan Stephens, María Eugenia de la Morena-Barrio, Luca Stefanucci, José Padilla, Antonia Miñano, Nicholas Gleadall, Juan Luis García, María Fernanda López-Fernández, Pierre-Emmanuel Morange, Marja K Puurun, Anetta Undas, Francisco Vidal, NIHR BioResource, F Lucy Raymond, Vicente Vicente García, Willem H Ouwehand, Javier Corral, Alba Sanchis-Juan.

The identification and characterization of structural variants (SVs) in clinical genetics have remained historically challenging as routine genetic diagnostic techniques have limited ability to evaluate repetitive regions and SVs. Long-read whole-genome sequencing (LR-WGS) has emerged as a powerful approach to resolve SVs.

Here, we used LR-WGS to study 19 unrelated cases with type I Antithrombin Deficiency (ATD), the most severe thrombophilia, where routine molecular tests were either negative, ambiguous, or not fully characterized. We developed an analysis workflow to identify disease-associated SVs and resolved 10 cases.

For the first time, we identified a germline complex rearrangement involved in ATD previously misclassified as a deletion. Additionally, we provided molecular diagnoses for two unresolved individuals that harbored a novel SINE-VNTR-Alu (SVA) retroelement insertion that we fully characterized by de novo assembly and confirmed by PCR amplification in all affected relatives.

Finally, the nucleotide-level resolution achieved for all the SVs allowed breakpoint analysis, which revealed a replication-based mechanism for most of the cases. Our study underscores the utility of LR-WGS as a complementary diagnostic method to identify, characterize, and unveil the molecular mechanism of formation of disease-causing SVs, and facilitates decision making about long-term thromboprophylaxis in ATD patients.

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