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. Frontiers in Immunology. LAUSANNE: FRONTIERS MEDIA SA, vol. 11, June 2020, p. 1-13. ISSN 1664-3224. doi:10.3389/fimmu.2020.00900. 2020.
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Basic information
Original name The Clinical and Genetic Spectrum of 82 Patients WithRAGDeficiency Including a c.256_257delAA Founder Variant in Slavic Countries
Authors SHARAPOVA, S. O. (112 Belarus, guarantor), M. SKOMSKA-PAWLISZAK (616 Poland), Y. A. RODINA (643 Russian Federation), B. WOLSKA-KUSNIERZ (616 Poland), N. DABROWSKA-LEONIK (616 Poland), B. MIKOLUC (616 Poland), O. E. PASHCHENKO (643 Russian Federation), S. PASIC (688 Serbia), Tomáš FREIBERGER (203 Czech Republic, belonging to the institution), T. MILOTA (203 Czech Republic), R. FORMANKOVA (203 Czech Republic), A. SZAFLARSKA (616 Poland), M. SIEDLAR (705 Slovenia), T. AVCIN (705 Slovenia), G. MARKELJ (705 Slovenia), P. CIZNAR (703 Slovakia), K. KALWAK (616 Poland), S. KOTTAN (616 Poland), T. JACKOWSKA (616 Poland), K. DRABKO (616 Poland), A. GAGRO (191 Croatia), M. PAC (616 Poland), E. NAUMOVA (100 Bulgaria), S. KANDILAROVA (100 Bulgaria), K. BABOL-POKORA (616 Poland), D. S. VARABYOU (112 Belarus), B. H. BARENDREGT (528 Netherlands), E. V. RAYKINA (643 Russian Federation), T. V. VARLAMOVA (643 Russian Federation), A. V. PAVLOVA (643 Russian Federation), Hana GROMBIŘÍKOVÁ (203 Czech Republic, belonging to the institution), M. DEBELJAK (703 Slovakia), I. V. MERSIYANOVA (643 Russian Federation), A. V BONDARENKO (804 Ukraine), L. I. CHERNYSHOVA (804 Ukraine), L. V. KOSTYUCHENKO (804 Ukraine), M. N. GUSEVA (643 Russian Federation), J. RASCON (440 Lithuania), A. MULEVICIENE (440 Lithuania), E. PREIKSAITIENE (440 Lithuania), C. B. GEIER (40 Austria), A. LEISS-PILLER (40 Austria), Y. YAMAZAKI (840 United States of America), T. KAWAI (840 United States of America), J. E. WALTER (840 United States of America), I.V. KONDRATENKO (643 Russian Federation), A. SEDIVA (203 Czech Republic), M. VAN DER BURG (528 Netherlands), N. B. KUZMENKO (643 Russian Federation), L. D. NOTARANGELO (840 United States of America), E. BERNATOWSKA (616 Poland) and O. V. ALEINIKOVA (112 Belarus).
Edition Frontiers in Immunology, LAUSANNE, FRONTIERS MEDIA SA, 2020, 1664-3224.
Other information
Original language English
Type of outcome Article in a journal
Field of Study 30102 Immunology
Country of publisher Switzerland
Confidentiality degree is not subject to a state or trade secret
WWW URL
Impact factor Impact factor: 7.561
RIV identification code RIV/00216224:14110/20:00116171
Organization unit Faculty of Medicine
Doi http://dx.doi.org/10.3389/fimmu.2020.00900
UT WoS 000546856100001
Keywords in English RAG1; RAG2; primary immunodeficiency; geographic distribution; incidence; Slavic children
Tags 14110114, rivok
Tags International impact, Reviewed
Changed by Changed by: Mgr. Tereza Miškechová, učo 341652. Changed: 10/8/2020 12:52.
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 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.
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