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.

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Journal
Journal of Human Immunity
Published
2025-12-22
DOI
https://doi.org/10.70962/lasid2025abstract.9
Primary Topic
Immunodeficiency and Autoimmune Disorders
Type
article
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article

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

Sinisa Savic, Faranaz Atschekzei, D.E. Potts, Andrej A. Petrov et al.
Journal of Human Immunity
Immunodeficiency and Autoimmune Disorders
article

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

Sinisa Savic, Faranaz Atschekzei, D.E. Potts, Andrej A. Petrov, Ravishankar Sargur, Jonathan M. Hernandez, Safa Baris, Dessislava I. Dimitrova, Eva Fronkova, Inga Sakovich, JE Walter, Manish J. Butte, David Buchbinder, Veronika Kanderová, Brant R. Ward, Klaus Warnatz, Elena A. Latysheva, SO Sharapova, J. Kanakry, Olajumoke Fadugba, Jean‐Pierre de Villartay, Cristina Maria Kokron, R.Z. Miller, Edward Morris, Hassan Abolhassani, Agustina Vasvari, C. Schuetz, T. Milota, E. Polykova, A. Sediva, C.B. Geier, E. Kuznetsova, Kevin A. Strauss, A. Bulkhi, C. Speckmann, S. Holland, S. Burns, L.D. Notarangelo, D. Moshous, M.H. Albert, P. Suhet, L. Mendonça, A. Cochino, T. Freiberger
article en

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.

Journal of Human ImmunityVol. 1(LASID2025)
Hôpital Necker-Enfants Malades (FR), Children's Hospital of Orange County (US), Clinic for Special Children (US), Children's National (US), Johns Hopkins University (US), University of California, Los Angeles (US), Royal Free London NHS Foundation Trust (GB), Universidade de São Paulo (BR), Favaloro University (AR), Umm al-Qura University (SA), Charles University (CZ), Masaryk University (CZ), Leeds Teaching Hospitals NHS Trust (GB), University Medical Center Freiburg (DE), Karolinska Institutet (SE), Medizinische Hochschule Hannover (DE), Institut Necker Enfants Malades (FR), University Hospital in Motol (CZ), Johns Hopkins All Children's Hospital (US), Sheffield Teaching Hospitals NHS Foundation Trust (GB), Pulmonary and Allergy Associates (US), Ministry of Health (MN), National Institute of Allergy and Infectious Diseases (US), University of Pittsburgh Medical Center (US), National Cancer Institute (US), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (BR), Belarusian Research Center For Pediatric Oncology and Hematology (BY), University Hospital Carl Gustav Carus (DE), Institut des Maladies Génétiques Imagine (FR), University College London (GB), Federal Medical-Biological Agency (RU), Marmara University (TR), University of South Florida St. Petersburg (US), University of Pennsylvania (US), Ludwig-Maximilians-Universität München (DE)
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Openalex Percentile: Top 37%
Immunodeficiency and Autoimmune Disorders
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