Clinical and Genetic Insights into Partial RAG Deficiency in Adults: When to Consider Hematopoietic Stem Cell Transplantation?

Introduction Recombinase activating gene (RAG) deficiency is an inborn error of immunity (IEI) due to mutations in RAG1/2, impairing band T cell receptor repertoire diversity. While typically linked to severe combined immunodeficiency (SCID) in children, partial RAG deficiency (pRD) is increasingly identified in adults with milder phenotypes, leading to delayed diagnosis and treatment challenges. This study aimed to characterize the clinical and genetic profiles of adults with pRD and examine factors influencing hematopoietic stem cell transplantation (HSCT) decision. Method A retrospective multicenter analysis was conducted on 35 adults with pRD (27 RAG1, 7 RAG2, 1 both). Data included demographics, clinical severity, complications, laboratory results, transplant indication, and outcomes. Results Patients (age 17–74; median 37) exhibited diverse phenotypes: CID with granulomas/autoimmunity (49%), common variable immune deficiency or antibody deficiency (26%), classical CID (11%), and asymptomatic (14%). Molecular diagnosis occurred in adulthood, with infections starting between ages 3–35. Eight patients underwent HSCT at a mean age of 35.8 years (range 24-42), due to progressive disease, severe granulomatous inflammation, autoimmunity, and chronic pulmonary involvement. Survival was 50% among those transplanted, with transplant-related complications. The 27 non-transplanted patients displayed heterogeneous severity. Five asymptomatic individuals remained clinically stable during follow-up. At the time of analysis, 13 of the 35 patients (37%) had died (age range 28–74), mostly from infections, respiratory failure, or malignancy. Overall survival in the cohort was 63% (22/35) underscoring the high burden of morbidity and mortality in adult patients with partial RAG deficiency, regardless of phenotype. Conclusions pRD in adults is underdiagnosed and clinically variable. Genetic testing supports diagnosis, but HSCT timing remains uncertain. Findings highlight the need for prognostic markers and early genetic screening in adults with atypical antibody deficiencies or recurrent infections. Gene therapy could become a feasible alternative in carefully selected cases.