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Introduction: The J Project (JP) physician education and clinical research collaboration program was started in 2004 and includes by now 32 countries mostly in Eastern and Central Europe (ECE). Until the end of 2021, 344 inborn errors of immunity (IEI)-focused meetings were organized by the JP to raise awareness and facilitate the diagnosis and treatment of patients with IEI., Results: In this study, meeting profiles and major diagnostic and treatment parameters were studied. JP center leaders reported patients' data from 30 countries representing a total population of 506 567 565. Two countries reported patients from JP centers (Konya, Turkey and Cairo University, Egypt). Diagnostic criteria were based on the 2020 update of classification by the IUIS Expert Committee on IEI. The number of JP meetings increased from 6 per year in 2004 and 2005 to 44 and 63 in 2020 and 2021, respectively. The cumulative number of meetings per country varied from 1 to 59 in various countries reflecting partly but not entirely the population of the respective countries. Altogether, 24,879 patients were reported giving an average prevalence of 4.9. Most of the patients had predominantly antibody deficiency (46,32%) followed by patients with combined immunodeficiencies (14.3%). The percentages of patients with bone marrow failure and phenocopies of IEI were less than 1 each. The number of patients was remarkably higher that those reported to the ESID Registry in 13 countries. Immunoglobulin (IgG) substitution was provided to 7,572 patients (5,693 intravenously) and 1,480 patients received hematopoietic stem cell therapy (HSCT). Searching for basic diagnostic parameters revealed the availability of immunochemistry and flow cytometry in 27 and 28 countries, respectively, and targeted gene sequencing and new generation sequencing was available in 21 and 18 countries. The number of IEI centers and experts in the field were 260 and 690, respectively. We found high correlation between the number of IEI centers and patients treated with intravenous IgG (IVIG) (correlation coefficient, cc, 0,916) and with those who were treated with HSCT (cc, 0,905). Similar correlation was found when the number of experts was compared with those treated with HSCT. However, the number of patients treated with subcutaneous Ig (SCIG) only slightly correlated with the number of experts (cc, 0,489) and no correlation was found between the number of centers and patients on SCIG (cc, 0,174)., Conclusions: 1) this is the first study describing major diagnostic and treatment parameters of IEI care in countries of the JP; 2) the data suggest that the JP had tremendous impact on the development of IEI care in ECE; 3) our data help to define major future targets of JP activity in various countries; 4) we suggest that the number of IEI centers and IEI experts closely correlate to the most important treatment parameters; 5) we propose that specialist education among medical professionals plays pivotal role in increasing levels of diagnostics and adequate care of this vulnerable and still highly neglected patient population; 6) this study also provides the basis for further analysis of more specific aspects of IEI care including genetic diagnostics, disease specific prevalence, newborn screening and professional collaboration in JP countries., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Abolhassani, Avcin, Bahceciler, Balashov, Bata, Bataneant, Belevtsev, Bernatowska, Bidló, Blazsó, Boisson, Bolkov, Bondarenko, Boyarchuk, Bundschu, Casanova, Chernishova, Ciznar, Csürke, Erdős, Farkas, Fomina, Galal, Goda, Guner, Hauser, Ilyina, Iremadze, Iritsyan, Ismaili-Jaha, Jesenak, Kelecic, Keles, Kindle, Kondratenko, Kostyuchenko, Kovzel, Kriván, Kuli-Lito, Kumánovics, Kurjane, Latysheva, Latysheva, Lázár, Markelj, Markovic, Maródi, Mammadova, Medvecz, Miltner, Mironska, Modell, Modell, Mosdósi, Mukhina, Murdjeva, Műzes, Nabieva, Nasrullayeva, Naumova, Nagy, Onozó, Orozbekova, Pac, Pagava, Pampura, Pasic, Petrosyan, Petrovic, Pocek, Prodeus, Reisli, Ress, Rezaei, Rodina, Rumyantsev, Sciuca, Sediva, Serban, Sharapova, Shcherbina, Sitkauskiene, Snimshchikova, Spahiu-Konjusha, Szolnoky, Szűcs, Toplak, Tóth, Tsyvkina, Tuzankina, Vlasova and Volokha.)

Introduction: Primary immunodeficiencies (PID) are a group of rare genetic disorders with a multitude of clinical symptoms. Characterization of epidemiological and clinical data via national registries has proven to be a valuable tool of studying these diseases. Materials and Methods: The Russian PID registry was set up in 2017, by the National Association of Experts in PID (NAEPID). It is a secure, internet-based database that includes detailed clinical, laboratory, and therapeutic data on PID patients of all ages. Results: The registry contained information on 2,728 patients (60% males, 40% females), from all Federal Districts of the Russian Federation. 1,851/2,728 (68%) were alive, 1,426/1,851 (77%) were children and 425/1,851 (23%) were adults. PID was diagnosed before the age of 18 in 2,192 patients (88%). Antibody defects (699; 26%) and syndromic PID (591; 22%) were the most common groups of PID. The minimum overall PID prevalence in the Russian population was 1.3:100,000 people; the estimated PID birth rate is 5.7 per 100,000 live births. The number of newly diagnosed patients per year increased dramatically, reaching the maximum of 331 patients in 2018. The overall mortality rate was 9.8%. Genetic testing has been performed in 1,740 patients and genetic defects were identified in 1,344 of them (77.2%). The median diagnostic delay was 2 years; this varied from 4 months to 11 years, depending on the PID category. The shortest time to diagnosis was noted in the combined PIDs-in WAS, DGS, and CGD. The longest delay was observed in AT, NBS, and in the most prevalent adult PID: HAE and CVID. Of the patients, 1,622 had symptomatic treatment information: 843 (52%) received IG treatment, mainly IVIG (96%), and 414 (25%) patients were treated with biological drugs. HSCT has been performed in 342/2,728 (16%) patients, of whom 67% are currently alive, 17% deceased, and 16% lost to follow-up. Three patients underwent gene therapy for WAS; all are currently alive. Conclusions: Here, we describe our first analysis of the epidemiological features of PID in Russia, allowing us to highlight the main challenges around PID diagnosis and treatment., (Copyright © 2020 Mukhina, Kuzmenko, Rodina, Kondratenko, Bologov, Latysheva, Prodeus, Pampura, Balashov, Ilyina, Latysheva, Deordieva, Shvets, Deripapa, Abramova, Pashenko, Vahlyarskaya, Zinovyeva, Zimin, Skorobogatova, Machneva, Fomina, Ipatova, Barycheva, Khachirova, Tuzankina, Bolkov, Shakhova, Kamaltynova, Sibgatullina, Guseva, Kuznetsova, Milichkina, Totolian, Kalinina, Goltsman, Sulima, Kutlyanceva, Moiseeva, Khoreva, Nesterenko, Tymofeeva, Ermakova, Proligina, Kalmetieva, Davletbaieva, Mirsayapova, Richkova, Kuzmicheva, Grakhova, Yudina, Orlova, Selezneva, Piskunova, Samofalova, Bukina, Pechkurova, Migacheva, Zhestkov, Barmina, Parfenova, Isakova, Averina, Sazonova, Starikova, Shilova, Asekretova, Suprun, Kleshchenko, Lebedev, Demikhova, Demikhov, Kalinkina, Gorenkova, Duryagina, Pavlova, Shinkareva, Smoleva, Aleksandrova, Bambaeva, Philippova, Gracheva, Tcyvkina, Efremenkov, Mashkovskaya, Yarovaya, Alekseenko, Fisyun, Molokova, Troitskya, Piatkina, Vlasova, Ukhanova, Chernishova, Vasilieva, Laba, Volodina, Safonova, Voronin, Gurkina, Rumyantsev, Novichkova and Shcherbina.)

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., (Copyright © 2020 Sharapova, Skomska-Pawliszak, Rodina, Wolska-Kuśnierz, Dabrowska-Leonik, Mikołuć, Pashchenko, Pasic, Freiberger, Milota, Formánková, Szaflarska, Siedlar, Avčin, Markelj, Ciznar, Kalwak, Kołtan, Jackowska, Drabko, Gagro, Pac, Naumova, Kandilarova, Babol-Pokora, Varabyou, Barendregt, Raykina, Varlamova, Pavlova, Grombirikova, Debeljak, Mersiyanova, Bondarenko, Chernyshova, Kostyuchenko, Guseva, Rascon, Muleviciene, Preiksaitiene, Geier, Leiss-Piller, Yamazaki, Kawai, Walter, Kondratenko, Šedivá, van der Burg, Kuzmenko, Notarangelo, Bernatowska and Aleinikova.)

Background: Omenn syndrome [Mendelian Inheritance (OMIM 603554)] is a genetic disease of the immune system, characterized by the presence of fatal generalized severe erythroderma, lymphoadenopathy, eosinophilia and profound immunodeficiency., Objective: We studied clinical and immunologic presentation of the disease manifestation among East Slavs population with genetically confirmed Omenn syndrome., Results: We collected clinical and immunologic data of 11 patients (1 from Belarus, 5--Ukraine, 5--Russia): 6 females, 5 males. The age of Omenn syndrome manifestation varied from the 1st day of life to 1 year and 1 month, the age of diagnosis--20 days to 1 year and 10 months. Nine out of 11 patients had classic immunologic phenotype T(+/-)B-NK+, 1 pt had TlowB + NK+ with CD3 + TCRgd + expansion and 1 had TlowB+/-NK+ phenotype. Eight out of 11 pts had mutation in RAG1 gene, 4 out of 8 had c.368-369delAA (p.K86fsX118) in homozygous state or heterozygous compound. In our cohort of patients, we also described two new mutations in RAG genes (p.E722Q in RAG1 and p.M459R in RAG2). At present, 7/11 were transplanted and 5 out of the transplanted are alive., Conclusion: This study demonstrates that the most popular genetic abnormality in East Slavs children with Omenn syndrome is c.368-369delAA (p.K86fs118) in RAG1 gene, which may be connected with more favorable prognosis because 4/4 patients survived after hematopoietic stem cells transplantation.