AUTHOR=Sharapova Svetlana O. , Skomska-Pawliszak Małgorzata , Rodina Yulia A. , Wolska-Kuśnierz Beata , Dabrowska-Leonik Nel , Mikołuć Bozena , Pashchenko Olga E. , Pasic Srdjan , Freiberger Tomáš , Milota Tomáš , Formánková Renata , Szaflarska Anna , Siedlar Maciej , Avčin Tadej , Markelj Gašper , Ciznar Peter , Kalwak Krzysztof , Kołtan Sylwia , Jackowska Teresa , Drabko Katarzyna , Gagro Alenka , Pac Małgorzata , Naumova Elissaveta , Kandilarova Snezhina , Babol-Pokora Katarzyna , Varabyou Dzmitry S. , Barendregt Barbara H. , Raykina Elena V. , Varlamova Tatiana V. , Pavlova Anna V. , Grombirikova Hana , Debeljak Maruša , Mersiyanova Irina V. , Bondarenko Anastasiia V. , Chernyshova Liudmyla I. , Kostyuchenko Larysa V. , Guseva Marina N. , Rascon Jelena , Muleviciene Audrone , Preiksaitiene Egle , Geier Christoph B. , Leiss-Piller Alexander , Yamazaki Yasuhiro , Kawai Tomoki , Walter Jolan E. , Kondratenko Irina V. , Šedivá Anna , van der Burg Mirjam , Kuzmenko Natalia B. , Notarangelo Luigi D. , Bernatowska Ewa , Aleinikova Olga V.
TITLE=The Clinical and Genetic Spectrum of 82 Patients With RAG Deficiency Including a c.256_257delAA Founder Variant in Slavic Countries
JOURNAL=Frontiers in Immunology
VOLUME=11
YEAR=2020
URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.00900
DOI=10.3389/fimmu.2020.00900
ISSN=1664-3224
ABSTRACT=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.