Recombination junctions from antibody isotype switching classify immune and DNA repair dysfunction

Personalized assessment of immunocompetence and DNA double-strand break (DSB) repair requires methods that are sensitive to genetic and molecular complexity beyond the well-known monogenic disorders. Inspired by decades of research using B cells to study DNA repair processes, here we present SWIBRID (SWItch junction Breakpoint Repertoire IDentification), a tool to systematically profile genomic junctions generated in vivo during antibody class switch recombination (CSR) in B cells. As CSR junctions reflect immune diversity and DNA repair proficiency, SWIBRID detects phenotypic manifestations of deficiencies via a highly scalable, blood-based PCR followed by long-read sequencing and bioinformatic analysis. We show that specific DNA repair defects, including cancer-associated mutations, exhibit distinct CSR junction patterns. Notably, SWIBRID distinguishes different types of DSB repair knockouts and identifies the respective genetic defect in cell lines. In 68 patients, we detect immunodeficiencies and DNA repair defects with high accuracy (area under the curve 0.99 and 0.84, respectively), and identify previously uncharacterized patient groups as well as patient-specific CSR junction signatures. With SWIBRID, we seek to advance the identification of pathogenic defects, support early diagnosis, and address molecular heterogeneity that drives variable clinical outcomes.

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Publication Details

Journal
Nature Communications
Published
2025-12-19
DOI
https://doi.org/10.1038/s41467-025-67206-5
Primary Topic
DNA Repair Mechanisms
Type
article
Field-Weighted Citation Impact
0.00

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article

Recombination junctions from antibody isotype switching classify immune and DNA repair dysfunction

Kathrin de la Rosa, Baerbel Keller, Klaus Warnatz, Dorothee Speiser et al.
Nature Communications
DNA Repair Mechanisms
article

Recombination junctions from antibody isotype switching classify immune and DNA repair dysfunction

Kathrin de la Rosa, Baerbel Keller, Klaus Warnatz, Dorothee Speiser, Michela Di Virgilio, Benedikt Obermayer, Hassan Abolhassani, Mikhail Lebedin, Qiang Pan‐Hammarström, Dieter Beule, Christoph Ratswohl, Clara Vázquez García, Stephan Mathas, Antonia Busse
article en

Abstract

Personalized assessment of immunocompetence and DNA double-strand break (DSB) repair requires methods that are sensitive to genetic and molecular complexity beyond the well-known monogenic disorders. Inspired by decades of research using B cells to study DNA repair processes, here we present SWIBRID (SWItch junction Breakpoint Repertoire IDentification), a tool to systematically profile genomic junctions generated in vivo during antibody class switch recombination (CSR) in B cells. As CSR junctions reflect immune diversity and DNA repair proficiency, SWIBRID detects phenotypic manifestations of deficiencies via a highly scalable, blood-based PCR followed by long-read sequencing and bioinformatic analysis. We show that specific DNA repair defects, including cancer-associated mutations, exhibit distinct CSR junction patterns. Notably, SWIBRID distinguishes different types of DSB repair knockouts and identifies the respective genetic defect in cell lines. In 68 patients, we detect immunodeficiencies and DNA repair defects with high accuracy (area under the curve 0.99 and 0.84, respectively), and identify previously uncharacterized patient groups as well as patient-specific CSR junction signatures. With SWIBRID, we seek to advance the identification of pathogenic defects, support early diagnosis, and address molecular heterogeneity that drives variable clinical outcomes.

Nature CommunicationsVol. 16(1)
Helmholtz Association of German Research Centres (DE), University of Freiburg (DE), German Cancer Research Center (DE), Max Delbrück Center (DE), University Medical Center Freiburg (DE), Karolinska Institutet (SE), Humboldt-Universität zu Berlin (DE), German Cancer Society (DE), Children's Medical Center (IR), Breast Center (CH), Helmholtz Centre for Infection Research (DE), Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE), Centre for Individualised Infection Medicine (DE), Freie Universität Berlin (DE), Charité - Universitätsmedizin Berlin (DE)
Deutsche Forschungsgemeinschaft
Openalex Percentile: Top 62%
DNA Repair Mechanisms
DOIOpen Access PDFOpenAlex
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