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The Clinical and Genetic Spectrum of 82 Patients With RAG Deficiency Including a c.256_257delAA Founder Variant in Slavic Countries
SO. Sharapova, M. Skomska-Pawliszak, YA. Rodina, B. Wolska-Kuśnierz, N. Dabrowska-Leonik, B. Mikołuć, OE. Pashchenko, S. Pasic, T. Freiberger, T. Milota, R. Formánková, A. Szaflarska, M. Siedlar, T. Avčin, G. Markelj, P. Ciznar, K. Kalwak, S....
Jazyk angličtina Země Švýcarsko
Typ dokumentu časopisecké články, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, práce podpořená grantem
Grantová podpora
R01 AI100887
NIAID NIH HHS - United States
NLK
Directory of Open Access Journals
od 2010
Free Medical Journals
od 2010
PubMed Central
od 2010
Europe PubMed Central
od 2010
Open Access Digital Library
od 2010-01-01
Open Access Digital Library
od 2010-01-01
ROAD: Directory of Open Access Scholarly Resources
od 2010
PubMed
32655540
DOI
10.3389/fimmu.2020.00900
Knihovny.cz E-zdroje
- MeSH
- běloši * MeSH
- dítě MeSH
- DNA vazebné proteiny genetika MeSH
- fenotyp MeSH
- frekvence genu MeSH
- genotyp * MeSH
- homeodoménové proteiny genetika MeSH
- incidence MeSH
- jaderné proteiny genetika MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- novorozenec MeSH
- polymorfismus genetický MeSH
- předškolní dítě MeSH
- retrospektivní studie MeSH
- sekvenční delece genetika MeSH
- syndromy imunologické nedostatečnosti genetika MeSH
- výsledek terapie MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- novorozenec MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, N.I.H., Intramural MeSH
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.
2nd Faculty of Medicine Charles University Prague Czechia
Center for Pediatric Oncology and Hematology Vilnius University Vilnius Lithuania
Centre for Cardiovascular Surgery and Transplantation Brno Czechia
Consulting Center of Pediatric Medical Academy St Petersburg Russia
Department of Clinical Immunology University Children's Hospital Krakow Poland
Department of Clinical Immunology University Hospital Alexandrovska Sofia Bulgaria
Department of Geographical Ecology Belarusian State University Minsk Belarus
Department of Immunology Children's Memorial Health Institute Warsaw Poland
Department of Immunology Erasmus MC University Medical Center Rotterdam Rotterdam Netherlands
Department of Immunology University Hospital Motol Prague Czechia
Department of Pediatric Hematology and Oncology University Hospital Motol Prague Czechia
Department of Pediatric Hematology Oncology and BMT Wroclaw Medical University Wroclaw Poland
Department of Pediatrics Hematology and Oncology Collegium Medicum in Bydgoszcz Bydgoszcz Poland
Department of Pediatrics Medical Center of Postgraduate Education Warsaw Poland
Department of Pediatrics Oncology and Hematology Medical University of Lodz Lodz Poland
Faculty of Medicine Charles University Prague Czechia
Faculty of Medicine Josip Juraj Strossmayer University of Osijek Osijek Croatia
Faculty of Medicine Masaryk University Brno Czechia
Faculty of Medicine University of Ljubljana Ljubljana Slovenia
Hematology Oncology and Transfusion Medicine Center Vilnius University Vilnius Lithuania
Immunology Department Pirogov Russian National Research Medical University Moscow Russia
Immunology Outpatient Clinic Vienna Austria
Massachusetts General Hospital for Children Boston MA United States
Nicolaus Copernicus University in Torun Torun Poland
Pediatric Department Faculty of Medicine Comenius University Bratislava Slovakia
Pediatric Department West Ukrainian Specialized Children's Medical Center Lviv Ukraine
University Children's Hospital University Medical Centre Ljubljana Ljubljana Slovenia
Citace poskytuje Crossref.org
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