TY  - JOUR
AU  - Vázquez García, Clara
AU  - Obermayer, Benedikt
AU  - Keller, Baerbel
AU  - Lebedin, Mikhail
AU  - Ratswohl, Christoph
AU  - Abolhassani, Hassan
AU  - Busse, Antonia
AU  - Di Virgilio, Michela
AU  - Mathas, Stephan
AU  - Speiser, Dorothee
AU  - Beule, Dieter
AU  - Pan-Hammarström, Qiang
AU  - Warnatz, Klaus
AU  - de la Rosa, Kathrin
TI  - Recombination junctions from antibody isotype switching classify immune and DNA repair dysfunction.
JO  - Nature Communications
VL  - nn
SN  - 2041-1723
CY  - [London]
PB  - Springer Nature
M1  - DKFZ-2025-03013
SP  - nn
PY  - 2025
N1  - epub
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:41419734
DO  - DOI:10.1038/s41467-025-67206-5
UR  - https://inrepo02.dkfz.de/record/307369
ER  -