What question did this study set out to answer?

This research aims to identify the role of a novel homozygous RAG1 variant in a child with EBV-negative Burkitt lymphoma and its implications for immune function.

January 17, 2026

Germline Homozygous RAG1 Missense Variant Associated With Epstein-Barr Virus Negative Childhood Burkitt Lymphoma

Key Points

This research aims to identify the role of a novel homozygous RAG1 variant in a child with EBV-negative Burkitt lymphoma and its implications for immune function.
Evaluated a 9-year-old male with cervical lymphadenopathy and Burkitt lymphoma diagnosis.
Performed whole-exome sequencing and Sanger validation to identify RAG1 variant.
Conducted immunologic testing including lymphocyte subset analysis and immunoglobulin level assessment.
Identified a homozygous RAG1 variant absent in population databases.
Patient had normal immunologic test results and did not show SCID features.
The patient responded well to chemotherapy and remains in remission.

Abstract

The recombination activating gene 1 (RAG1) is essential for V (D) J recombination and lymphocyte development. While biallelic null RAG1 mutations cause severe combined immunodeficiency (SCID), hypomorphic variants have increasingly been associated with immune dysregulation and hematologic malignancies. This study aimed to present a pediatric case of Epstein-Barr virus (EBV) -negative Burkitt lymphoma carrying a novel homozygous RAG1 variant and to discuss its potential association with immune function and malignancy risk. A 9-year-old Turkish male from a consanguineous family was evaluated for hereditary cancer predisposition. Clinical, immunologic, and genetic assessments were performed, including whole-exome sequencing (WES), Sanger validation, and mRNA expression analysis. The patient presented with cervical lymphadenopathy and was diagnosed with EBV-negative Burkitt lymphoma; he had no recurrent infections, abnormal vaccine reactions, or SCID-related features. Immunologic testing, including lymphocyte subsets and immunoglobulin levels, was within normal limits. WES identified a homozygous RAG1 variant (NM₀00448. 2: c. 460C>T; p. Leu154Phe), predicted to be deleterious and absent from population databases. Both the patient and his healthy dizygotic twin were homozygous, while parents were heterozygous carriers. RAG1 mRNA expression was reduced in heterozygotes but similar in homozygous and wild-type individuals; enzymatic activity was not assessed. The patient responded to chemotherapy and remains in remission under follow-up. In conclusion, this case expands the phenotypic spectrum of hypomorphic RAG1 variants to include EBV-negative Burkitt lymphoma without overt immunodeficiency, suggesting a possible link between partial RAG1 dysfunction and pediatric lymphoma susceptibility.

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