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

J 2020

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

SHARAPOVA, S. O., M. SKOMSKA-PAWLISZAK, Y. A. RODINA, B. WOLSKA-KUSNIERZ, N. DABROWSKA-LEONIK et. al.

Základní údaje

Originální název

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

Autoři

SHARAPOVA, S. O. (112 Bělorusko, garant), M. SKOMSKA-PAWLISZAK (616 Polsko), Y. A. RODINA (643 Rusko), B. WOLSKA-KUSNIERZ (616 Polsko), N. DABROWSKA-LEONIK (616 Polsko), B. MIKOLUC (616 Polsko), O. E. PASHCHENKO (643 Rusko), S. PASIC (688 Srbsko), Tomáš FREIBERGER (203 Česká republika, domácí), T. MILOTA (203 Česká republika), R. FORMANKOVA (203 Česká republika), A. SZAFLARSKA (616 Polsko), M. SIEDLAR (705 Slovinsko), T. AVCIN (705 Slovinsko), G. MARKELJ (705 Slovinsko), P. CIZNAR (703 Slovensko), K. KALWAK (616 Polsko), S. KOTTAN (616 Polsko), T. JACKOWSKA (616 Polsko), K. DRABKO (616 Polsko), A. GAGRO (191 Chorvatsko), M. PAC (616 Polsko), E. NAUMOVA (100 Bulharsko), S. KANDILAROVA (100 Bulharsko), K. BABOL-POKORA (616 Polsko), D. S. VARABYOU (112 Bělorusko), B. H. BARENDREGT (528 Nizozemské království), E. V. RAYKINA (643 Rusko), T. V. VARLAMOVA (643 Rusko), A. V. PAVLOVA (643 Rusko), Hana GROMBIŘÍKOVÁ (203 Česká republika, domácí), M. DEBELJAK (703 Slovensko), I. V. MERSIYANOVA (643 Rusko), A. V BONDARENKO (804 Ukrajina), L. I. CHERNYSHOVA (804 Ukrajina), L. V. KOSTYUCHENKO (804 Ukrajina), M. N. GUSEVA (643 Rusko), J. RASCON (440 Litva), A. MULEVICIENE (440 Litva), E. PREIKSAITIENE (440 Litva), C. B. GEIER (40 Rakousko), A. LEISS-PILLER (40 Rakousko), Y. YAMAZAKI (840 Spojené státy), T. KAWAI (840 Spojené státy), J. E. WALTER (840 Spojené státy), I.V. KONDRATENKO (643 Rusko), A. SEDIVA (203 Česká republika), M. VAN DER BURG (528 Nizozemské království), N. B. KUZMENKO (643 Rusko), L. D. NOTARANGELO (840 Spojené státy), E. BERNATOWSKA (616 Polsko) a O. V. ALEINIKOVA (112 Bělorusko)

Vydání

Frontiers in Immunology, LAUSANNE, FRONTIERS MEDIA SA, 2020, 1664-3224

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

30102 Immunology

Stát vydavatele

Švýcarsko

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 7.561

Kód RIV

RIV/00216224:14110/20:00116171

Organizační jednotka

Lékařská fakulta

DOI

http://dx.doi.org/10.3389/fimmu.2020.00900

UT WoS

000546856100001

Klíčová slova anglicky

RAG1; RAG2; primary immunodeficiency; geographic distribution; incidence; Slavic children

Štítky

14110114, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 10. 8. 2020 12:52, Mgr. Tereza Miškechová

Anotace

V originále

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.

Citovat

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 a 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, 2020, roč. 11, June 2020, s. 1-13. ISSN 1664-3224. Dostupné z: https://dx.doi.org/10.3389/fimmu.2020.00900.

@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 a 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, roč.~11, June 2020, s.~1-13. ISSN~1664-3224. Dostupné z: https://dx.doi.org/10.3389/fimmu.2020.00900.

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