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@article{1673759, author = {Sharapova, S. O. and SkomskaandPawliszak, M. and Rodina, Y. A. and WolskaandKusnierz, B. and DabrowskaandLeonik, N. and Mikoluc, B. and Pashchenko, O. E. and Pasic, S. and Freiberger, Tomáš and Milota, T. and Formankova, R. and Szaflarska, A. and Siedlar, M. and Avcin, T. and Markelj, G. and Ciznar, P. and Kalwak, K. and Kottan, S. and Jackowska, T. and Drabko, K. and Gagro, A. and Pac, M. and Naumova, E. and Kandilarova, S. and BabolandPokora, K. and Varabyou, D. S. and Barendregt, B. H. and Raykina, E. V. and Varlamova, T. V. and Pavlova, A. V. and Grombiříková, Hana and Debeljak, M. and Mersiyanova, I. V. and Bondarenko, A. V and Chernyshova, L. I. and Kostyuchenko, L. V. and Guseva, M. N. and Rascon, J. and Muleviciene, A. and Preiksaitiene, E. and Geier, C. B. and LeissandPiller, A. and Yamazaki, Y. and Kawai, T. and Walter, J. E. and Kondratenko, I.V. and Sediva, A. and van Der Burg, M. and Kuzmenko, N. B. and Notarangelo, L. D. and Bernatowska, E. and Aleinikova, O. V.}, article_location = {LAUSANNE}, article_number = {June 2020}, doi = {http://dx.doi.org/10.3389/fimmu.2020.00900}, keywords = {RAG1; RAG2; primary immunodeficiency; geographic distribution; incidence; Slavic children}, language = {eng}, issn = {1664-3224}, journal = {Frontiers in Immunology}, title = {The Clinical and Genetic Spectrum of 82 Patients WithRAGDeficiency Including a c.256_257delAA Founder Variant in Slavic Countries}, url = {https://www.frontiersin.org/articles/10.3389/fimmu.2020.00900/full}, volume = {11}, year = {2020} }
TY - JOUR ID - 1673759 AU - Sharapova, S. O. - Skomska-Pawliszak, M. - Rodina, Y. A. - Wolska-Kusnierz, B. - Dabrowska-Leonik, N. - Mikoluc, B. - Pashchenko, O. E. - Pasic, S. - Freiberger, Tomáš - Milota, T. - Formankova, R. - Szaflarska, A. - Siedlar, M. - Avcin, T. - Markelj, G. - Ciznar, P. - Kalwak, K. - Kottan, S. - Jackowska, T. - Drabko, K. - Gagro, A. - Pac, M. - Naumova, E. - Kandilarova, S. - Babol-Pokora, K. - Varabyou, D. S. - Barendregt, B. H. - Raykina, E. V. - Varlamova, T. V. - Pavlova, A. V. - Grombiříková, Hana - Debeljak, M. - Mersiyanova, I. V. - Bondarenko, A. V - Chernyshova, L. I. - Kostyuchenko, L. V. - Guseva, M. N. - Rascon, J. - Muleviciene, A. - Preiksaitiene, E. - Geier, C. B. - Leiss-Piller, A. - Yamazaki, Y. - Kawai, T. - Walter, J. E. - Kondratenko, I.V. - Sediva, A. - van Der Burg, M. - Kuzmenko, N. B. - Notarangelo, L. D. - Bernatowska, E. - Aleinikova, O. V. PY - 2020 TI - The Clinical and Genetic Spectrum of 82 Patients WithRAGDeficiency Including a c.256_257delAA Founder Variant in Slavic Countries JF - Frontiers in Immunology VL - 11 IS - June 2020 SP - 1-13 EP - 1-13 PB - FRONTIERS MEDIA SA SN - 16643224 KW - RAG1 KW - RAG2 KW - primary immunodeficiency KW - geographic distribution KW - incidence KW - Slavic children UR - https://www.frontiersin.org/articles/10.3389/fimmu.2020.00900/full L2 - https://www.frontiersin.org/articles/10.3389/fimmu.2020.00900/full N2 - 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 theRAGdefects in populations inhabiting South, West, and East Slavic countries. Methods:Demographic, clinical, and laboratory data were collected fromRAG-deficient patients of Slavic origin via chart review, retrospectively. Recombinase activity was determinedin vitroby flow cytometry-based assay. Results:Based on the clinical and immunologic phenotype, our cohort of 82 patients from 68 families represented a wide spectrum ofRAGdeficiencies, including SCID (n= 20), OS (n= 37), and LS/CID (n= 25) phenotypes. Sixty-seven (81.7%) patients carriedRAG1and 15 patients (18.3%) carriedRAG2biallelic variants. We estimate that the minimal annual incidence ofRAGdeficiency 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 withRAG1variants 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 homozygousRAG1p.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 homozygousRAG1p.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 thatRAG1p.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 ofRAG1founder 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. ER -
SHARAPOVA, S. O., M. SKOMSKA-PAWLISZAK, Y. A. RODINA, B. WOLSKA-KUSNIERZ, N. DABROWSKA-LEONIK, B. MIKOLUC, O. E. PASHCHENKO, S. PASIC, Tomáš FREIBERGER, T. MILOTA, R. FORMANKOVA, A. SZAFLARSKA, M. SIEDLAR, T. AVCIN, G. MARKELJ, P. CIZNAR, K. KALWAK, S. KOTTAN, T. JACKOWSKA, K. DRABKO, A. GAGRO, M. PAC, E. NAUMOVA, S. KANDILAROVA, K. BABOL-POKORA, D. S. VARABYOU, B. H. BARENDREGT, E. V. RAYKINA, T. V. VARLAMOVA, A. V. PAVLOVA, Hana GROMBIŘÍKOVÁ, M. DEBELJAK, I. V. MERSIYANOVA, A. V BONDARENKO, L. I. CHERNYSHOVA, L. V. KOSTYUCHENKO, M. N. GUSEVA, J. RASCON, A. MULEVICIENE, E. PREIKSAITIENE, C. B. GEIER, A. LEISS-PILLER, Y. YAMAZAKI, T. KAWAI, J. E. WALTER, I.V. KONDRATENKO, A. SEDIVA, M. VAN DER BURG, N. B. KUZMENKO, L. D. NOTARANGELO, E. BERNATOWSKA and O. V. ALEINIKOVA. The Clinical and Genetic Spectrum of 82 Patients WithRAGDeficiency Including a c.256\_{}257delAA Founder Variant in Slavic Countries. \textit{Frontiers in Immunology}. LAUSANNE: FRONTIERS MEDIA SA, 2020, vol.~11, June 2020, p.~1-13. ISSN~1664-3224. Available from: https://dx.doi.org/10.3389/fimmu.2020.00900.
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