Background: Variants in recombination-activating genes (RAG) are common genetic causes of autosomal recessive forms of combined immunodeficiencies (CID) ranging from severe combined immunodeficiency (SCID), Omenn syndrome (OS), leaky SCID, and CID with granulomas and/or autoimmunity (CID-G/AI), and even milder presentation with antibody deficiency. Objective: We aim to estimate the incidence, clinical presentation, genetic variability, and treatment outcome with geographic distribution of patients with the RAG defects in populations inhabiting South, West, and East Slavic countries. Methods: Demographic, clinical, and laboratory data were collected from RAG-deficient patients of Slavic origin via chart review, retrospectively. Recombinase activity was determined in vitro by flow cytometry-based assay. Results: Based on the clinical and immunologic phenotype, our cohort of 82 patients from 68 families represented a wide spectrum of RAG deficiencies, including SCID (n = 20), OS (n = 37), and LS/CID (n = 25) phenotypes. Sixty-seven (81.7%) patients carried RAG1 and 15 patients (18.3%) carried RAG2 biallelic variants. We estimate that the minimal annual incidence of RAG deficiency in Slavic countries varies between 1 in 180,000 and 1 in 300,000 live births, and it may vary secondary to health care disparities in these regions. In our cohort, 70% (n = 47) of patients with RAG1 variants carried p.K86Vfs*33 (c.256_257delAA) allele, either in homozygous (n = 18, 27%) or in compound heterozygous (n = 29, 43%) form. The majority (77%) of patients with homozygous RAG1 p.K86Vfs*33 variant originated from Vistula watershed area in Central and Eastern Poland, and compound heterozygote cases were distributed among all Slavic countries except Bulgaria. Clinical and immunological presentation of homozygous RAG1 p.K86Vfs*33 cases was highly diverse (SCID, OS, and AS/CID) suggestive of strong influence of additional genetic and/or epigenetic factors in shaping the final phenotype. Conclusion: We propose that RAG1 p.K86Vfs*33 is a founder variant originating from the Vistula watershed region in Poland, which may explain a high proportion of homozygous cases from Central and Eastern Poland and the presence of the variant in all Slavs. Our studies in this cohort of RAG1 founder variants confirm that clinical and immunological phenotypes only partially depend on the underlying genetic defect. As access to HSCT is improving among RAG-deficient patients in Eastern Europe, we anticipate improvements in survival.

2nd Faculty of Medicine Charles University Prague Czechia

Center for Pediatric Oncology and Hematology Vilnius University Vilnius Lithuania

Centre for Cardiovascular Surgery and Transplantation Brno Czechia

Consulting Center of Pediatric Medical Academy St Petersburg Russia

Department of Clinical Immunology Institute of Pediatrics Jagiellonian University Medical College Krakow Poland

Department of Clinical Immunology Russian Clinical Children's Hospital by Pirogov Russian National Research Medical University Moscow Russia

Department of Clinical Immunology University Children's Hospital Krakow Poland

Department of Clinical Immunology University Hospital Alexandrovska Sofia Bulgaria

Department of Epidemiology and Monitoring of Primary Immunodeficiencies Dmitry Rogachev National Medical Research Center of Pediatric Hematology Oncology and Immunology Moscow Russia

Department of Geographical Ecology Belarusian State University Minsk Belarus

Department of Immunology Children's Memorial Health Institute Warsaw Poland

Department of Immunology Dmitry Rogachev National Medical Research Center of Pediatric Hematology Oncology and Immunology Moscow Russia

Department of Immunology Erasmus MC University Medical Center Rotterdam Rotterdam Netherlands

Department of Immunology University Hospital Motol Prague Czechia

Department of Pediatric Hematology and Oncology University Hospital Motol Prague Czechia

Department of Pediatric Hematology Oncology and BMT Wroclaw Medical University Wroclaw Poland

Department of Pediatric Hematology Oncology and Transplantology Medical University of Lublin Lublin Poland

Department of Pediatric Infectious Diseases and Pediatric Immunology Shupyk National Medical Academy for Postgraduate Education Kiev Ukraine

Department of Pediatric Laboratory for Pediatric Immunology Willem Alexander Children's Hospital LUMC Leiden Netherlands

Department of Pediatrics Hematology and Oncology Collegium Medicum in Bydgoszcz Bydgoszcz Poland

Department of Pediatrics Medical Center of Postgraduate Education Warsaw Poland

Department of Pediatrics Oncology and Hematology Medical University of Lodz Lodz Poland

Department of Pediatrics Rheumatology Immunology and Metabolic Bone Diseases Medical University of Bialystok Bialystok Poland

Department of Pediatrics School of Medicine Zagreb Children's Hospital University of Zagreb Zagreb Croatia

Faculty of Medicine Charles University Prague Czechia

Faculty of Medicine Josip Juraj Strossmayer University of Osijek Osijek Croatia

Faculty of Medicine Masaryk University Brno Czechia

Faculty of Medicine University of Ljubljana Ljubljana Slovenia

Hematology Oncology and Transfusion Medicine Center Vilnius University Vilnius Lithuania

Immunology Department Pirogov Russian National Research Medical University Moscow Russia

Immunology Outpatient Clinic Vienna Austria

Laboratory of Clinical Immunology and Microbiology Division of Intramural Research National Institute of Allergy and Infectious Diseases National Institutes of Health Bethesda MD United States

Laboratory of Molecular Biology Dmitry Rogachev National Medical Research Center of Pediatric Hematology Oncology and Immunology Moscow Russia

Massachusetts General Hospital for Children Boston MA United States

Nicolaus Copernicus University in Torun Torun Poland

Pediatric Department Faculty of Medicine Comenius University Bratislava Slovakia

Pediatric Department West Ukrainian Specialized Children's Medical Center Lviv Ukraine

Pediatric Immunology Medical Faculty Mother and Child Health Institute University of Belgrade Belgrade Serbia

Research Department Belarusian Research Center for Pediatric Oncology Hematology and Immunology Minsk Region Belarus

University Children's Hospital University Medical Centre Ljubljana Ljubljana Slovenia

University of South Florida at Johns Hopkins All Children's Hospital Saint Petersburg FL United States

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