The Clinical and Genetic Spectrum of 82 Patients With RAG Deficiency Including a c.256_257delAA Founder Variant in Slavic Countries

<b>Background:</b> Variants in recombination-activating genes (<i>RAG</i>) 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. <b>Objective:</b> We aim to estimate the incidence, clinical presentation, genetic variability, and treatment outcome with geographic distribution of patients with the <i>RAG</i> defects in populations inhabiting South, West, and East Slavic countries. <b>Methods:</b> Demographic, clinical, and laboratory data were collected from <i>RAG</i>-deficient patients of Slavic origin via chart review, retrospectively. Recombinase activity was determined <i>in vitro</i> by flow cytometry-based assay. <b>Results:</b> Based on the clinical and immunologic phenotype, our cohort of 82 patients from 68 families represented a wide spectrum of <i>RAG</i> deficiencies, including SCID (<i>n</i> = 20), OS (<i>n</i> = 37), and LS/CID (<i>n</i> = 25) phenotypes. Sixty-seven (81.7%) patients carried <i>RAG1</i> and 15 patients (18.3%) carried <i>RAG2</i> biallelic variants. We estimate that the minimal annual incidence of <i>RAG</i> 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% (<i>n</i> = 47) of patients with <i>RAG1</i> variants carried p.K86Vfs^*33 (c.256_257delAA) allele, either in homozygous (<i>n</i> = 18, 27%) or in compound heterozygous (<i>n</i> = 29, 43%) form. The majority (77%) of patients with homozygous <i>RAG1</i> 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 <i>RAG1</i> 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. <b>Conclusion:</b> We propose that <i>RAG1</i> 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 <i>RAG1</i> 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.