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

Variants in recombination-activating genes () 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. We aim to estimate the incidence, clinical presentation, genetic variability, and treatment outcome with geographic distribution of patients with the defects in populations inhabiting South, West, and East Slavic countries. Demographic, clinical, and laboratory data were collected from -deficient patients of Slavic origin via chart review, retrospectively. Recombinase activity was determined by flow cytometry-based assay. Based on the clinical and immunologic phenotype, our cohort of 82 patients from 68 families represented a wide spectrum of deficiencies, including SCID ( = 20), OS ( = 37), and LS/CID ( = 25) phenotypes. Sixty-seven (81.7%) patients carried and 15 patients (18.3%) carried biallelic variants. We estimate that the minimal annual incidence of 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% ( = 47) of patients with variants carried p.K86Vfs33 (c.256_257delAA) allele, either in homozygous ( = 18, 27%) or in compound heterozygous ( = 29, 43%) form. The majority (77%) of patients with homozygous p.K86Vfs33 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 p.K86Vfs33 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. We propose that p.K86Vfs33 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 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.