Immunogenetics最新文献

{"title":"Sequence variants underlying severe combined immunodeficiency and leukocyte adhesion deficiency type 1 in six consanguineous families","authors":"Hajra Fayyaz, Atteaya Zaman, Nighat Haider, Rehmana Waris, Muhammad Hussain, Syed Irfan Raza, Wasim Ahmad, Imran Ullah","doi":"10.1007/s00251-024-01353-9","DOIUrl":"https://doi.org/10.1007/s00251-024-01353-9","url":null,"abstract":"<p>Inborn errors of immunity (IEI) are defined as genetic disorders affecting the immune system and resulting in diverse clinical signs and symptoms. Despite the lack of diagnosis and unavailability of IEI estimation in the Pakistani population, consanguinity is exacerbating its prevalence. The current study focuses on severe combined immunodeficiency (SCID) and leukocyte adhesion deficiency type 1 (LAD1). SCID is associated with the life-threatening symptoms developing at post-birth. LAD1 is clinically characterized by recurrent bacterial infections related to the skin, mouth, and respiratory tract owing to impaired leukocytes. Herein, in six consanguineous families, flow cytometry was used to evaluate the patient’s immune status. Whole-exome sequencing (WES) was then conducted to search for the causative variations in immunodeficiency genes. Sanger sequencing was used to assess the segregation of the variants with the disorder within the families. Sequence analysis revealed five homozygous variants in four different causative genes. This included four novel nonsense variants in <i>CD70</i> p.(Thr126Profs*33), <i>CD3e</i> p.(Trp151*), <i>IL7R</i> p.(Val138Ilefs*10), and <i>ITGB2</i> p.(Ser627Valfs*61), and one previously reported in <i>ITGB2</i> p.(Cys62*). In one of the families, two variants in two different genes, including <i>DNAH6</i> p.(Tyr2653His) and <i>NIPAL4</i> p.(Gly121Ser), were detected in an unclassified patient. All the identified variants were found in a homozygous state in the patient but in a heterozygous state in the available parents. The study will facilitate the diagnosis and management of IEI patients.</p>","PeriodicalId":13446,"journal":{"name":"Immunogenetics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142261443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potential contribution of gut microbiota in the development of autoantibodies in T1D children carrying HLA-DRB1/DQB1 risk alleles: an experimental and in silico analysis","authors":"Ata Shirizadeh, Zahra Razavi, Vahid Saeedi, Mahdi Behzad, Javad Faradmal, Ghasem Solgi","doi":"10.1007/s00251-024-01354-8","DOIUrl":"https://doi.org/10.1007/s00251-024-01354-8","url":null,"abstract":"<p>This study aimed to investigate the prevalence of insulin autoantibody (IAA), glutamic acid decarboxylase antibody (GADA), and insulinoma-associated antigen-2 antibody (IA-2A) in type 1 diabetes (T1D) children based on the presence of predisposing <i>HLA-II</i> alleles. Additionally, to assess the sequence homology between autoantigens of islet cells and selected proteins derived from gut bacteria in terms of their binding capacities to <i>HLA</i> risk alleles, <i>HLA-DRB1/DQB1</i> alleles were determined by PCR-SSOP in 111 T1D children (probands) along with 222 parents and 133 siblings. Autoantibodies were measured by ELISA, and in silico analysis was run as follows: protein extraction, homology and epitope prediction, peptide alignment, and HLA-peptide docking. Higher significant frequencies of <i>DRB1*03:01</i>, <i>DQB1*02:01</i>, and <i>DQB1*03:02</i> alleles and <i>DRB1*03:01</i> ~ <i>DQB1*02:01</i> haplotype and lower frequencies of <i>DRB1*11:01</i>, <i>DRB1*14:01</i>, and <i>DQB1*03:01</i> alleles were found in probands compared to parents and siblings. <i>DRB1*11:01</i> ~ <i>DQB1*03:01</i>, <i>DRB1*14:01</i> ~ <i>DQB1*05:03</i>, and <i>DRB1*15:01-DQB1*06:02</i> haplotypes were significantly less frequent in the probands compared to parents. Out of 111 probands, 21 were seronegative, 90 tested positive for one autoantibody, and 15 showed the concurrent presence of three autoantibodies. Logistic regression analysis revealed that <i>DRB1*04</i> ~ <i>DQB1*03:02</i> haplotype was associated with the induction of GADA and IA-2A, while <i>DRB1*11:01</i> ~ <i>DQB1*03:01</i> was associated with seronegativity. Epitopes derived from GAD and gut bacteria showed strong binding capacities to <i>HLA</i> risk alleles. Due to the sequence similarities between gut bacteria-derived proteins and islet cell autoantigens and their potential for binding to <i>HLA</i> risk alleles, dysbiosis of gut microbiota can be considered another risk factor for the development of T1D, especially in genetically susceptible individuals.</p>","PeriodicalId":13446,"journal":{"name":"Immunogenetics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142261444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A possible role of lncRNA MEG3 and lncRNA MAFG-AS1 on miRNA 147-b in the pathogenesis of Behcet's disease.","authors":"Shimaa Abobakr, Olfat Shaker, Mohamed Tharwat Hegazy, Ayman Mohamed Hany","doi":"10.1007/s00251-024-01346-8","DOIUrl":"10.1007/s00251-024-01346-8","url":null,"abstract":"<p><p>Behcet's disease (BD) is a multisystem disease with altered Toll-like receptors (TLRs) on macrophages. Long noncoding RNA Maternally expressed gene 3 (lncRNA MEG3) and lncRNA Musculoaponeurotic fibrosarcoma oncogene family, protein G antisense 1 (MAFG-AS1) are regulators of microRNA (miRNA) 147-b, which is induced upon TLR stimulation. We included fifty BD patients, and fifty age and sex-matched controls. Real-time polymerase chain reaction (PCR) was used to measure the expression levels of serum lncRNA MEG3, lncRNA MAFG-AS1, and miRNA 147-b. LncRNA MEG3 and lncRNA MAFG-AS1 were significantly downregulated while miRNA 147-b was significantly upregulated in the BD patients' serum compared to the controls with p-value <0.001. Receiver operation characteristics (ROC) curve analysis revealed that the three biomarkers can discriminate between BD and control subjects with 76%, 100%, and 70% sensitivity respectively, and 100% specificity for all of them. There was a lower expression level of lnc RNA MEG3 among patients who had new eye involvement in the last month in comparison to those without new eye involvement (p-value=0.017). So, LncRNA MEG3, lncRNA MAFG-AS1, and miRNA147-b are promising diagnostic markers and therapeutic targets for BD patients. LncRNA MEG3 can be used as a predictor for new BD ocular involvement.</p>","PeriodicalId":13446,"journal":{"name":"Immunogenetics","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11246302/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141563326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Associations between immune cell traits and autoimmune thyroid diseases: a bidirectional two-sample mendelian randomization study.","authors":"ZheXu Cao, JiangSheng Huang, Xia Long","doi":"10.1007/s00251-024-01345-9","DOIUrl":"10.1007/s00251-024-01345-9","url":null,"abstract":"<p><p>Autoimmune thyroid diseases (AITDs), mainly including Graves' disease (GD) and Hashimoto's thyroiditis (HT), are common autoimmune disorders characterized by abnormal immune responses targeting the thyroid gland. We conducted a bidirectional two-sample MR analysis using the largest dataset of peripheral immune cell phenotypes from Sardinia, and the AITD dataset from the 10th round of the FinnGen and the UK Biobank project. Instrumental variables (IVs) were rigorously selected based on the three assumptions of MR and analyzed using the Wald ratio, inverse-variance weighted (IVW), MR-Egger, and weighted median methods. Additionally, sensitivity analyses were performed using Cochrane's Q, the Egger intercept, the MR-PRESSO, and the leave-one-out (LOO) method to ensure the robustness of the results. The Steiger test was utilized to identify and exclude potential reverse causation. The results showed that 3, 3, and 11 immune cell phenotypes were significantly associated with the risk of AITD. In GD, the proportion of naive CD4-CD8- (DN) T cells in T cells and the proportion of terminally differentiated CD4+T cells in T cells showed the strongest inducing and protective effects, respectively. In HT, lymphocyte count and CD45 on CD4+T cells showed the strongest inducing and protective effects, respectively. In autoimmune hypothyroidism, CD127 CD8+T cell count and terminally differentiated DN T cell count exhibited the strongest inducing and protective effects, respectively. Through MR analysis, our study provides direct genetic evidence of the impact of immune cell traits on AITD risk and lays the groundwork for potential therapeutic and diagnostic target discovery.</p>","PeriodicalId":13446,"journal":{"name":"Immunogenetics","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141467710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HLA alleles, haplotypes frequencies, and their association with hematological disorders: a report from 1550 families whose patients underwent allogeneic bone marrow transplantation in Egypt.","authors":"Yasser ElNahass, Nourhan Mekky, Nabil M Abdelfattah, Raafat Abdelfattah, Mohamed Samra, Omar A Fahmy, Gamal Fathy, Wafaa Elmetnawy, Salwa Sabet, Heba Bassiouny, Heba Nader, Alaa ElHaddad, H K Mahmoud","doi":"10.1007/s00251-024-01343-x","DOIUrl":"10.1007/s00251-024-01343-x","url":null,"abstract":"<p><p>HLA alleles are representative of ethnicities and may play important roles in predisposition to hematological disorders. We analyzed DNA samples for HLA-A, -B, -C, -DRB1, and -DQB1 loci, from 1550 patients and 4450 potential related donors by PCR-SSO (Polymerase chain reaction sequence-specific oligonucleotides) and estimated allele frequencies in donors and patients from 1550 families who underwent bone marrow transplantation (BMT) in Egypt. We also studied the association between HLA allele frequencies and incidence of acute myeloid leukemia, acute lymphoblastic leukemia, and severe aplastic anemia. The most frequently observed HLA class I alleles were HLA- A*01:01 (16.9%), A*02:01 (16.1%), B*41:01 (8.7%), B*49:01 (7.3%), C*06:02 (25.1%), and C*07:01 (25.1%), and the most frequently observed class II alleles were HLA-DRB1*11:01 (11.8%), DRB1*03:01 (11.6%), DQB1*03:01 (27.5%), and DQB1*05:01 (18.9%). The most frequently observed haplotypes were A*33:01~B*14:02 ~ DRB1*01:02 (2.35%) and A*01:01~B*52:01~DRB1*15:01 (2.11%). HLA-DRB1*07:01 was associated with higher AML odds (OR, 1.26; 95% CI, 1.02-1.55; p = 0.030). Only HLA-B38 antigen showed a trend towards increased odds of ALL (OR, 1.52; 95% CI, 1.00-2.30; p = 0.049) HLA-A*02:01, -B*14:02, and -DRB1*15:01 were associated with higher odds of SAA (A*02:01: OR, 1.35; 95% CI, 1.07-1.70; p = 0.010; B*14:02: OR, 1.43; 95% CI, 1.06-1.93; p = 0.020; DRB1*15:01: OR, 1.32; 95% CI, 1.07-1.64; p = 0.011). This study provides estimates of HLA allele and haplotype frequencies and their association with hematological disorders in an Egyptian population.</p>","PeriodicalId":13446,"journal":{"name":"Immunogenetics","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141431821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dog leukocyte antigen genotyping across class I and class II genes in beagle dogs as laboratory animals.","authors":"Hiroya Konno, Jiro Miyamae, Hiroko Kataoka, Makoto Akai, Hiroaki Miida, Yoshimi Tsuchiya","doi":"10.1007/s00251-024-01344-w","DOIUrl":"10.1007/s00251-024-01344-w","url":null,"abstract":"<p><p>Dog leukocyte antigen (DLA) polymorphisms have been found to be associated with inter-individual variations in the risk, susceptibility, and severity of immune-related phenomena. While DLA class II genes have been extensively studied, less research has been performed on the polymorphisms of DLA class I genes, especially in beagle dogs commonly used as laboratory animals for safety evaluations in drug development. We genotyped four DLA class I genes and four DLA class II genes by locus-specific Sanger sequencing using 93 laboratory beagle dogs derived from two different strains: TOYO and Marshall. The results showed that, for DLA class I genes, 11, 4, 1, and 2 alleles, including a novel allele, were detected in DLA-88, DLA-12/88L, DLA-64, and DLA-79, while, for DLA class II genes, 1, 10, 6, and 7 alleles were detected in DLA-DRA, DLA-DRB1, DLA-DQA1, and DLA-DQB1, respectively. It was estimated that there were 14 DLA haplotypes, six of which had a frequency of ≥ 5%. Furthermore, when comparing the DLA diversity between TOYO and Marshall strains, the most common alleles and haplotypes differed between them. This is the first study to genotype all DLA loci and determine DLA haplotypes including all DLA class I and class II genes in dogs. Integrating information on the DLA diversity of laboratory beagle dogs should reinforce their benefit as an animal model for understanding various diseases associated with a specific DLA type.</p>","PeriodicalId":13446,"journal":{"name":"Immunogenetics","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141450417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evolutionary divergence of TLR9 through ancestral sequence reconstruction.","authors":"Manisha Ghosh, Surajit Basak, Shanta Dutta","doi":"10.1007/s00251-024-01338-8","DOIUrl":"10.1007/s00251-024-01338-8","url":null,"abstract":"<p><p>The transmembrane pattern recognition receptor, Toll-like receptor (TLR), are best known for their roles in innate immunity via recognition of pathogen and initiation of signaling response. Mammalian TLRs recognize molecular patterns associated with pathogens and initiate innate immune response. We have studied the evolutionary diversity of mammalian TLR genes for differences in immunological response. Reconstruction of ancestral sequences is a key aspect of the molecular evolution of TLR to track changes across the TLR genes. The comprehensive analysis of mammalian TLRs revealed a distinct pattern of evolution of TLR9. Various sequence-based features such as amino acid usage, hydrophobicity, GC content, and evolutionary constraints are found to influence the divergence of TLR9 from other TLRs. Ancestral sequence reconstruction analysis also revealed that the gradual evolution of TLR genes in several ancestral lineages leads to the distinct pattern of TLR9. It demonstrates evolutionary divergence with the progressive accumulation of mutations results in the distinct pattern of TLR9.</p>","PeriodicalId":13446,"journal":{"name":"Immunogenetics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140027979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lack of Syndecan-1 promotes the pathogenesis of experimental rheumatoid arthritis.","authors":"Rosalyn Jurjus, Laura Dosh, Rima Farhat, Tatiana Daccache, Jad El Masri, Maya Ghazi, Jihad Hawi, Angelo Leone, Abdo Jurjus","doi":"10.1007/s00251-024-01337-9","DOIUrl":"10.1007/s00251-024-01337-9","url":null,"abstract":"<p><p>Syndecan-1 (Sdc-1), a transmembrane heparan sulfate protein, is implicated in several pathophysiological processes including rheumatoid arthritis (RA). The exact role of Syndican-1 in this autoimmune disease is still undetermined. This study explores the involvement level of Sdc-1 in the development of RA in a collagen II-induced arthritis mice model. RA was induced in two mice strains (wild-type BALB/c group and Sdc-1 knockout) by collagen II. Mice underwent regular clinical observations and scoring. After sacrifice, leg biopsies were taken from mice for histological examination, using a variety of stains. In addition, proteins were extracted, and molecular assessment of TNF-α was performed using the western blot technique. In the Sdc-1 knockout group, clinical scoring results showed a significantly more severe experimental RA; histology showed a significant increase in bone erosion, cartilage destruction, inflammation, and less granulated mast cells than the wild-type. In addition, molecular assessment of TNF-α showed more increase in expression in the Sdc-1 knockout models compared to the wild-type. Data suggest that lack of Sdc-1 enhances the inflammatory characteristics in RA. However, more molecular studies and investigations are needed to determine its exact role and possible mechanisms involved.</p>","PeriodicalId":13446,"journal":{"name":"Immunogenetics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140049365","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HLA class I NK-epitopes and KIR diversities in patients with multiple myeloma.","authors":"Nicky A Beelen, Stefan J J Molenbroeck, Lisette Groeneveld, Christien E Voorter, Gerard M J Bos, Lotte Wieten","doi":"10.1007/s00251-024-01336-w","DOIUrl":"10.1007/s00251-024-01336-w","url":null,"abstract":"<p><p>Multiple myeloma (MM) is a hematological malignancy caused by the clonal expansion of malignant plasma cells in the bone marrow. Myeloma cells are susceptible to killing by natural killer (NK) cells, but NK cells fail to control disease progression, suggesting immunosuppression. The activation threshold of NK-effector function is regulated by interaction between KIRs and self-HLA class I, during a process called \"education\" to ensure self-tolerance. NK cells can respond to diseased cells based on the absence of HLA class I expression (\"Missing-self\" hypothesis). The HLA and KIR repertoire is extremely diverse; thus, the present study aimed to characterize potential variances in genotypic composition of HLA Class I NK-epitopes and KIRs between MM patients and healthy controls. Genotypic expression of KIR and HLA (HLA-C group-C1/C2 and Bw4 motifs (including HLA-A*23, A*24, A*32) were analyzed in 172 MM patients and 195 healthy controls. Compared to healthy controls, we did not observe specific KIR genes or genotypes, or HLA NK-epitopes with higher prevalence among MM patients. The presence of all three HLA NK-epitopes (C1⁺C2⁺Bw4⁺) was not associated with MM occurrence. However, MM patients were more likely to be C1^-/C2⁺/Bw4⁺ (p = 0.049, OR 1.996). In line with this, there was a trend of increased genetic co-occurrence of Bw4 and KIR3DL1 in MM patients (p = 0.05, OR 1.557). Furthermore, MM patients were more likely to genetically express both C2/KIR2DL1 and Bw4/KIR3DL1 (p = 0.019, OR 2.453). Our results reveal an HLA NK-epitope combination that is associated with the occurrence of MM. No specific KIR genotypes were associated with MM.</p>","PeriodicalId":13446,"journal":{"name":"Immunogenetics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11087314/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140119375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"B-cells absence in patients diagnosed as inborn errors of immunity: a registry-based study","authors":"Razieh Khoshnevisan, Shakiba Hassanzadeh, Christoph Klein, Meino Rohlfs, Bodo Grimbacher, Newsha Molavi, Aryana Zamanifar, Ali Khoshnevisan, Mahbube Jafari, Bahram Bagherpour, Mahdiyeh Behnam, Somayeh Najafi, Roya Sherkat","doi":"10.1007/s00251-024-01342-y","DOIUrl":"https://doi.org/10.1007/s00251-024-01342-y","url":null,"abstract":"<p>Hypogammaglobulinemia without B-cells is a subgroup of inborn errors of immunity (IEI) which is characterized by a significant decline in all serum immunoglobulin isotypes, coupled with a pronounced reduction or absence of B-cells. Approximately 80 to 90% of individuals exhibit genetic variations in Bruton’s agammaglobulinemia tyrosine kinase (BTK), whereas a minority of cases, around 5–10%, are autosomal recessive agammaglobulinemia (ARA). Very few cases are grouped into distinct subcategories. We evaluated phenotypically and genetically 27 patients from 13 distinct families with hypogammaglobinemia and no B-cells. Genetic analysis was performed via whole-exome and Sanger sequencing. The most prevalent genetic cause was mutations in <i>BTK</i>. Three novel mutations in the <i>BTK</i> gene include c.115 T &gt; C (p. Tyr39His), c.685-686insTTAC (p.Asn229llefs5), and c.163delT (p.Ser55GlnfsTer2). Our three ARA patients include a novel homozygous stop-gain mutation in the immunoglobulin heavy constant Mu chain (<i>IGHM</i>) gene, a novel frameshift mutation of the B-cell antigen receptor complex-associated protein (<i>CD79A</i>) gene, a novel bi-allelic stop-gain mutation in the transcription factor 3 (<i>TCF3</i>) gene. Three patients with agammaglobulinemia have an autosomal dominant inheritance pattern, which includes a missense variant in <i>PIK3CD</i>, a novel missense variant in <i>PIK3R1</i> and a homozygous silent mutation in the phosphoinositide-3-kinase regulatory subunit (<i>RASGRP1</i>) gene. This study broadens the genetic spectrum of hypogammaglobulinemia without B-cells and presented a few novel variants within the Iranian community, which may also have implications in other Middle Eastern populations. Notably, disease control was better in the second affected family member in families with multiple cases.</p>","PeriodicalId":13446,"journal":{"name":"Immunogenetics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140809120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}