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An Update on Inborn Errors of V(D)J Recombination

Lookup NU author(s): Dr Ina Schim van der LoeffORCiD, Dr Manisha AhujaORCiD, Dr Rui ChenORCiD, Eleonora Patane, Professor Sophie HambletonORCiD

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Abstract

V(D)J recombination is the fundamental process by which developing T and B lymphocytes generate diverse antigen receptors, enabling adaptive immunity. This tightly regulated program operates exclusively in lymphoid precursors during G1 phase and depends on the lymphocyte-specific RAG1-RAG2 recombinase to introduce programmed DNA double-strand breaks at recombination signal sequences, followed by repair through the classical nonhomologous end joining (c-NHEJ) pathway. Disruption of any step in this molecular choreography compromises antigen receptor diversity and underlies a spectrum of inborn errors of immunity (IEIs), ranging from severe combined immunodeficiency (SCID) to immune dysregulation with autoimmunity and granulomatous disease. In this review, we place disorders of V(D)J recombination within the broader framework of T-cell development, detailing the temporal waves of recombinase activity, chromatin accessibility, and DNA damage responses that guide thymocyte differentiation. We discuss pathogenic variants affecting the cleavage phase [RAG1, RAG2, and the recently identified RAG cochaperone NudC domain-containing 3 (NUDCD3)], end processing (ARTEMIS), ligation and repair (LIG4, XLF, XRCC4, PRKDC), and genome surveillance pathways (ATM, MRN complex, RNF168), highlighting genotype-phenotype correlations and mechanisms driving immune deficiency and dysregulation. We briefly review recent diagnostic advances, including newborn screening using T-cell receptor excision circles, repertoire sequencing, and functional assays, alongside current therapeutic strategies. Finally, we outline key unanswered questions and argue that continued integration of clinical observation with molecular discovery is essential to improve outcomes and deepen understanding of adaptive immune development.

Publication metadata

Author(s): Schim van der Loeff I, Ahuja M, Chen R, Patane E, Hambleton S

Publication type: Review

Publication status: Published

Journal: Physiology

Year: 2026

Volume: 41

Issue: 6

Print publication date: 01/11/2026

Online publication date: 28/03/2026

Acceptance date: 21/03/2026

ISSN (print): 1548-9213

ISSN (electronic): 1548-9221

URL: https://doi.org/10.1152/physiol.00004.2026

DOI: 10.1152/physiol.00004.2026

PubMed id: 41902554

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