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Introduction: Inborn errors of immunity (IEI) represent a heterogeneous large group of genetic disorders characterized by susceptibility of affected individuals to recurrent infections, autoimmune/inflammatory diseases, allergies and malignancy. We aim to report for the first time the Algerian registry for IEI in children.Methods: We describe the characteristics of IEI in Algerian children from the data collected in the Algerian registry for IEI over a long period of 37 years.Results: Between 1985 and 2021, we included 887 children (530 male, 59.6%) with a mean age at diagnosis of 3.23y and a mean diagnosis delay of 2y. The prevalence rate was estimated at 1.97/100,000 inhabitants or 5.91/100,000 children. The parental consanguinity was found in 52.6%. The most prevalent category was combined immunodeficiencies (CID) (35.5%) followed by predominantly antibody deficiencies (24.4%) and CID with syndromic features (17.9%). The most predominant diseases were severe CID (120 cases), MHC II deficiency (99 cases), agammaglobulinemia (81 cases), common variable immunodeficiency (74 cases), hyper IgE syndromes (60 patients), ataxia telangiectasia (46 patients), Wiskott Aldrich syndrome (40 patients) and chronic granulomatous disease (39 cases). The clinical presentation was dominated by lower respiratory tract infections (69%), failure to thrive (38.3%) and chronic diarrhea (35.2%). Genetic analysis was performed in 156 patients (17.6%). The global mortality rate was 28.4% mainly caused by CID.Conclusion: This is the first report of the Algerian registry for IEI in children. Data is globally similar to that of Middle East and North African (MENA) registries with high consanguinity, predominance of CID, and significant mortality. This registry highlights the weak points that should be improved in order to provide better patient care.

Human inborn errors of immunity (IEI) are a group of 485 distinct genetic disorders affecting children and adults. Signs and symptoms of IEI are heterogeneous, and accurate diagnosis can be challenging and depends on the available human expertise and laboratory resources. The Middle East and North Africa (MENA) region has an increased prevalence of IEI because of the high rate of consanguinity with a predominance of autosomal recessive disorders. This area also exhibits more severe disease phenotypes compared with other regions, probably due to the delay in diagnosis. The MENA-IEI registry network has designed protocols and guidelines for the diagnosis and treatment of IEI, taking into consideration the variable regional expertise and resources. These guidelines are primarily meant to improve the care of patients within the region, but can also be followed in other regions with similar patient populations.

Autosomal recessive agammaglobulinemia (ARA) is a primary immunodeficiency characterized by absent peripheral B cells, severe hypogammaglobulinemia, and absent BTK gene mutations. In ARA, mutations occur in genes encoding the pre-B cell receptor (pre-BCR) or downstream signaling proteins. In this work, we used candidate gene and whole-exome sequencing to investigate the molecular basis of ARA in 6 patients from 4 consanguineous North-African families. Sanger sequencing of candidate genes encoding the pre-BCR components (ΙGΗΜ, CD79A, CD79B, IGLL1, and VPREB1) was initially performed and determined the genetic defect in five patients. Two novel mutations in IGHM (p.Val378Alafs*1 and p.Ile184Serfs*21) were identified in three patients from two unrelated kindred and a novel nonsense mutation was identified in CD79A (p.Trp66*) in two siblings from a third kindred. Whole-exome sequencing (WES) was performed on the sixth patient who harbored a homozygous stop mutation at position 407 in the RAG2 gene (p.Glu407*). We concluded that conventional gene sequencing, especially when multiple genes are involved in the defect as is the case in ARA, is costly and time-consuming, resulting in delayed diagnosis that contributes to increased morbidity and mortality. In addition, it fails to identify the involvement of novel and unsuspected gene defects when the phenotype of the patients is atypical. WES has the potential to provide a rapid and more accurate genetic diagnosis in ARA, which is crucial for the treatment of the patients.

Aim Maturity-onset diabetes of the young (MODY) is a genetically and clinically heterogeneous group of autosomal dominantly inherited nonketotic diabetes. MODY2 or (GCK-MODY) subtype is caused by heterozygous mutations in the GCK gene coding for glucokinase. In our current study, we aim to confirm a clinically suspected GCK-MODY phenotype at molecular level and subsequently, to estimate co-segregation of the detected mutation with hyperglycemia among Algerian related subjects. Lastly, assessment of mutation effect was performed using a combination of computational tools. Methods Sixteen related subjects were implicated in this study (proband and 15 relatives). Blood samples were used for biochemical, immunological and genetic assays. The proband was screened for mutation in the GCK gene using PCR-sequencing technique. Mutation screening among proband's relatives was performed by PCR-Restriction fragment length polymorphism (PCR-RFLP) technique. Computational analysis was performed with a combination of predictive tools to assess effect of the detected mutation on glucokinase structure/function and stability. Results Genetic analysis results revealed the presence of c.253A>T (p.R85W) GCK mutation at heterozygous state in 11 subjects, while it was absent in 5 others. Biochemical analysis showed that all subjects carrying the p.R85W mutation were affected with diabetes or impaired fasting glucose (fasting glucose 6.94 ± 0.63 mmol/l, HbA1c 6.92 ± 0.77%), whereas the five non-carriers were normoglycemic (fasting glucose 5.01 ± 0.26 mmol/l, HbA1c 5.36 ± 0.17%). All computational tools predict the detected mutation to be ‘damaging’ or ‘probably damaging’ with high scores. Conclusion The p.R85W GCK mutation segregates with diabetes or IFG in a large pedigree. Clinical features of Algerian GCK-MODY patients are similar to those of other populations; in case of double diabetes the co-occurring diabetes overcomes the GCK-MODY phenotype. In silico predictions results are consistent with metabolic study.

Background Inborn errors of immunity (IEIs) are a heterogeneous group of genetic defects of immunity, which cause high rates of morbidity and mortality mainly among children due to infectious and non-infectious complications. The IEI burden has been critically underestimated in countries from middle- and low-income regions and the majority of patients with IEI in these regions lack a molecular diagnosis. Methods We analyzed the clinical, immunologic, and genetic data of IEI patients from 22 countries in the Middle East and North Africa (MENA) region. The data was collected from national registries and diverse databases such as the Asian Pacific Society for Immunodeficiencies (APSID) registry, African Society for Immunodeficiencies (ASID) registry, Jeffrey Modell Foundation (JMF) registry, J Project centers, and International Consortium on Immune Deficiency (ICID) centers. Results We identified 17,120 patients with IEI, among which females represented 39.4%. Parental consanguinity was present in 60.5% of cases and 27.3% of the patients were from families with a confirmed previous family history of IEI. The median age of patients at the onset of disease was 36 months and the median delay in diagnosis was 41 months. The rate of registered IEI patients ranges between 0.02 and 7.58 per 100,000 population, and the lowest rates were in countries with the highest rates of disability-adjusted life years (DALY) and death rates for children. Predominantly antibody deficiencies were the most frequent IEI entities diagnosed in 41.2% of the cohort. Among 5871 patients genetically evaluated, the diagnostic yield was 83% with the majority (65.2%) having autosomal recessive defects. The mortality rate was the highest in patients with non-syndromic combined immunodeficiency (51.7%, median age: 3.5 years) and particularly in patients with mutations in specific genes associated with this phenotype (RFXANK, RAG1, and IL2RG). Conclusions This comprehensive registry highlights the importance of a detailed investigation of IEI patients in the MENA region. The high yield of genetic diagnosis of IEI in this region has important implications for prevention, prognosis, treatment, and resource allocation., Karolinska Institute, Open access funding provided by Karolinska Institute.

Leukocyte adhesion deficiency type I (LAD-I) is an autosomal recessive disease characterized by impaired leukocyte diapedesis to sites of infection. The disorder is caused by mutations in the ITGB2 (integrin beta-2) gene. Herein, we report the first series of Algerian patients with LAD-I. In this study, we enrolled twelve patients. All suffered from the severe form of the disease, with no significant delay in umbilical cord separation, except for two patients, however omphalitis was present in most cases. The analysis of the spectrum of mutations showed three different homozygous mutations, two were known mutations (missense mutation: c.533C˃T and nonsense mutation: c.562C > T) and one was novel nonsense mutation (c.1401C > A). Thus, the three mutations affect CD18 and are responsible for the severe form of the disease.

International audience; Background : Chronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by inborn errors of the phagocyte nicotinamide adenine dinucleotide phosphate oxidase complex. From the first year of life onward, most affected patients display multiple, severe, and recurrent infections caused by bacteria and fungi. Mycobacterial infections have also been reported in some patients.Objective : Our objective was to assess the effect of mycobacterial disease in patients with CGD.Methods : We analyzed retrospectively the clinical features of mycobacterial disease in 71 patients with CGD. Tuberculosis and BCG disease were diagnosed on the basis of microbiological, pathological, and/or clinical criteria.Results : Thirty-one (44%) patients had tuberculosis, and 53 (75%) presented with adverse effects of BCG vaccination; 13 (18%) had both tuberculosis and BCG infections. None of these patients displayed clinical disease caused by environmental mycobacteria, Mycobacterium leprae, or Mycobacterium ulcerans. Most patients (76%) also had other pyogenic and fungal infections, but 24% presented solely with mycobacterial disease. Most patients presented a single localized episode of mycobacterial disease (37%), but recurrence (18%), disseminated disease (27%), and even death (18%) were also observed. One common feature in these patients was an early age at presentation for BCG disease. Mycobacterial disease was the first clinical manifestation of CGD in 60% of these patients.Conclusion : Mycobacterial disease is relatively common in patients with CGD living in countries in which tuberculosis is endemic, BCG vaccine is mandatory, or both. Adverse reactions to BCG and severe forms of tuberculosis should lead to a suspicion of CGD. BCG vaccine is contraindicated in patients with CGD.

International audience; X-linked agammagobulinemia (XLA) is a primary immunodeficiency caused by Bruton's tyrosine kinase (BTK) gene defect. XLA patients have absent or reduced number of peripheral B cells and a profound deficiency in all immunoglobulin isotypes. This multicenter study reports the clinical, immunological and molecular features of Bruton's disease in 40 North African male patients. Fifty male out of 63 (male and female) patients diagnosed with serum agammaglobulinemia and non detectable to less than 2 % peripheral B cells were enrolled. The search for BTK gene mutations was performed for all of them by genomic DNA amplification and Sanger sequencing. We identified 33 different mutations in the BTK gene in 40 patients including 12 missense mutations, 6 nonsense mutations, 6 splice-site mutations, 5 frameshift, 2 large deletions, one complex mutation and one in-frame deletion. Seventeen of these mutations are novel. This large series shows a lower frequency of XLA among male patients from North Africa with agammaglobulinemia and absent to low B cells compared with other international studies (63.5 % vs 85 %). No strong evidence for genotype-phenotype correlation was observed. This study adds to other reports from highly consanguineous North African populations, showing lower frequency of X-linked forms as compared to AR forms of the same primary immunodeficiency. Furthermore, a large number of novel BTK mutations were identified and could further help identify carriers for genetic counseling.

Primary immunodeficiencies (PIDs) are heritable disorders of immune system function. These defects are rare, but seem to be more frequent in populations with high consanguinity. The defect may affect T cells, B cells, phagocyte cells or complement proteins. Patients have increased susceptibility to recurrent infections, and may suffer from, allergy, auto-immune disorders or cancers. The assessment of 303 patients suspected to have a primary immunodeficiency during seven years (January 2003 to July 2010) allowed us to diagnose 75 PIDs aged between 3 months and 32 years: 51 (68%) males and 24 (32%) females; the sex ratio is 2.12. 40 % of the patients are the offspring of consanguineous marriages. The immunological tests that we used include measurment of serum IgG, IgA, IgM, IgE levels and IgG subclass levels; tetrazolium nitroblue test; lymphocyte immunophenotyping and flow cytometry evaluation of surface proteins as: CD11, CD15, CD18, MHC class II, CD40, CD40 ligand, CD25. We report in this study the results from the 75 patients: 13 have “severe combined immunodeficiency (SCID), 11: MHC II deficiency, 30: agammaglobulinaemia, 1: Hyper-IgM syndrome, 9: common variable immunodeficiency, 1: IgG2 deficiency, 9: phagocyte defects, and 1 ataxia-telangiectasia. The molecular characterization of these deficiencies is important for diagnosis in some cases, for prenatal diagnosis and for potential therapeutic intervention strategies. We plan to set up other tests for evaluation of the other PIDs.