1. The Clinical and Genetic Spectrum of 82 Patients With RAG Deficiency Including a c.256_257delAA Founder Variant in Slavic Countries
- Author
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Sharapova, S.O. (Svetlana O.), Skomska-Pawliszak, M. (Małgorzata), Rodina, Y.A. (Yulia A.), Wolska-Kusnierz, B. (Beata), Dabrowska-Leonik, N. (Nel), Mikoluc, B. (Bozena), Pashchenko, O.E. (Olga E.), Pasic, S. (Srdjan), Freiberger, T. (Tomáš), Milota, T. (Tomáš), Formánková, R. (Renata), Szaflarska, A. (Anna), Siedlar, M. (Maciej), Avcin, T. (Tadej), Markelj, G. (Gašper), Ciznar, P. (P.), Kalwak, K. (Krzysztof), Kołtan, S. (Sylwia), Jackowska, T. (Teresa), Drabko, K. (Katarzyna), Gagro, A. (Alenka), Pac, M. (Malgorzata), Naumova, E. (Elissaveta), Kandilarova, S. (Snezhina), Babol-Pokora, K. (Katarzyna), Varabyou, D.S. (Dzmitry S.), Barendregt, B.H. (Barbara), Raykina, E.V. (Elena V.), Varlamova, T.V. (Tatiana V.), Pavlova, A.V. (Anna V.), Grombirikova, H. (Hana), Debeljak, M. (Maruša), Mersiyanova, I.V. (Irina V.), Bondarenko, A.V. (Anastasiia V.), Chernyshova, L.I. (Liudmyla I.), Kostyuchenko, L. (Larysa), Guseva, M. (Marina), Rascon, J. (Jelena), Muleviciene, A. (Audrone), Preiksaitiene, E. (Egle), Geier, C.B. (Christoph B.), Leiss-Piller, A. (Alexander), Yamazaki, Y. (Yasuhiro), Kawai, T. (Tomoki), Walter, J.E. (Jolan E.), Kondratenko, I. (Irina), Sediva, A. (A.), Burg, M. (Mirjam) van der, Kuzmenko, N.B. (Natalia B.), Notarangelo, L.D. (Luigi Daniele), Bernatowska, E. (Ewa), Aleinikova, O. (O.), Sharapova, S.O. (Svetlana O.), Skomska-Pawliszak, M. (Małgorzata), Rodina, Y.A. (Yulia A.), Wolska-Kusnierz, B. (Beata), Dabrowska-Leonik, N. (Nel), Mikoluc, B. (Bozena), Pashchenko, O.E. (Olga E.), Pasic, S. (Srdjan), Freiberger, T. (Tomáš), Milota, T. (Tomáš), Formánková, R. (Renata), Szaflarska, A. (Anna), Siedlar, M. (Maciej), Avcin, T. (Tadej), Markelj, G. (Gašper), Ciznar, P. (P.), Kalwak, K. (Krzysztof), Kołtan, S. (Sylwia), Jackowska, T. (Teresa), Drabko, K. (Katarzyna), Gagro, A. (Alenka), Pac, M. (Malgorzata), Naumova, E. (Elissaveta), Kandilarova, S. (Snezhina), Babol-Pokora, K. (Katarzyna), Varabyou, D.S. (Dzmitry S.), Barendregt, B.H. (Barbara), Raykina, E.V. (Elena V.), Varlamova, T.V. (Tatiana V.), Pavlova, A.V. (Anna V.), Grombirikova, H. (Hana), Debeljak, M. (Maruša), Mersiyanova, I.V. (Irina V.), Bondarenko, A.V. (Anastasiia V.), Chernyshova, L.I. (Liudmyla I.), Kostyuchenko, L. (Larysa), Guseva, M. (Marina), Rascon, J. (Jelena), Muleviciene, A. (Audrone), Preiksaitiene, E. (Egle), Geier, C.B. (Christoph B.), Leiss-Piller, A. (Alexander), Yamazaki, Y. (Yasuhiro), Kawai, T. (Tomoki), Walter, J.E. (Jolan E.), Kondratenko, I. (Irina), Sediva, A. (A.), Burg, M. (Mirjam) van der, Kuzmenko, N.B. (Natalia B.), Notarangelo, L.D. (Luigi Daniele), Bernatowska, E. (Ewa), and Aleinikova, O. (O.)
- 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. Con
- Published
- 2020
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