Clinical and Genetic Insights into Partial RAG Deficiency in Adults: When to Consider Hematopoietic Stem Cell Transplantation?
Year: 2025
Type: article
Study design: Observational Study
Abstract: 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.
Source: Journal of Human Immunity
Authors: R.Z. Miller, A. Vasvari, D.E. Potts, D. Dimitrova, P. Suhet, H. Abolhassani, F. Atschekzei, A. Bulkhi, S. Burns, A. Cochino, M. Butte, O. Fadugba, T. Freiberger, E. Fronkova, C.B. Geier, J. Hernandez, S. Holland, V. Kanderova, E. Kuznetsova, E. Latysheva, T. Milota, D. Moshous, E. Polykova, I. Sakovich, R. Sargur, A. Sediva, S. Savic, C. Speckmann, J. De Villartay, B. Ward, K. Warnatz, J.A. Kanakry, E.C. Morris, M.H. Albert, D. Buchbinder, L. Mendonça, S. Baris, A. Petrov, C. Kokron, Kevin A. Strauss, L.D. Notarangelo, C. Schuetz, S.O. Sharapova, J.E. Walter
Institutions: Johns Hopkins All Children's Hospital, University of South Florida St. Petersburg, Favaloro University, National Institutes of Health, National Cancer Institute, Karolinska Institutet, Medizinische Hochschule Hannover, Umm al-Qura University, Royal Free London NHS Foundation Trust, University College London, University of California, Los Angeles, University of Pennsylvania, Masaryk University, Centrum kardiovaskulární a transplantační chirurgie, Charles University, University Hospital in Motol, University of Freiburg, University Medical Center Freiburg, National Institute of Allergy and Infectious Diseases, Ministry of Health of the Russian Federation, Federal Medical-Biological Agency, Hôpital Necker-Enfants Malades, Institut Necker Enfants Malades, Assistance Publique – Hôpitaux de Paris, Institut des Maladies Génétiques Imagine, Belarusian Research Center For Pediatric Oncology and Hematology, Sheffield Teaching Hospitals NHS Foundation Trust, Leeds Teaching Hospitals NHS Trust, St James's University Hospital, Children's National, Ludwig-Maximilians-Universität München, Children's Hospital of Orange County, University of California, Irvine, Universidade de São Paulo, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Marmara University, University of Pittsburgh, UPMC Health System, University of Pittsburgh Medical Center, University Hospital Carl Gustav Carus, Technische Universität Dresden
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: diamond
OpenAlex ID: W7116777442
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