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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

bioRxiv, ISSN: 2692-8205
2020
  • 3
    Citations
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Metrics Details

  • Citations
    3
    • Citation Indexes
      3
      • CrossRef
        3

Article Description

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.

Bibliographic Details

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

Cold Spring Harbor Laboratory

Biochemistry, Genetics and Molecular Biology; Agricultural and Biological Sciences; Immunology and Microbiology; Neuroscience; Pharmacology, Toxicology and Pharmaceutics

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