Current Genetic Defects in Common Variable Immune Deficiency Patients on the Geography Between Europe and Asia

Current Genetic Defects in Common Variable Immune Deficiency Patients on the Geography Between Europe and Asia | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Current Genetic Defects in Common Variable Immune Deficiency Patients on the Geography Between Europe and Asia Ayse Aygun, Ezgi Topyıldız, Mehmet Geyik, Neslihan Edeer Karaca, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3093761/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Identification of the causes of monogenetic common variable immune deficiency (CVID) patients has rapidly increased in the last years by means of worldwide availability of appropriate genetic diagnostic methods. However, up to date, very limited numbers of reports demostrating the role of geography, ethnicity and consanguinity have been published. Here, we reported the first study of Turkish CVID patients and compared them with the results of three countries from America, Europe and Asia. A total of 100 children diagnosed as CVID according to the criteria of European Society for Immunodeficiencies were enrolled and they were genetically analyzed by using Targeted Next Generation Sequencing and Whole Exome Sequencing. The median age of our patients was 5.8 years (range, 3.0-16.0 years) at clinical diagnosis and 9.0 years (range, 4.8-21.0 years) at the time of genetic diagnosis. The consanguianity rate was 24%. Disease-causing pathogenic mutations were defined in 40% of patients in a total of 17 different genes. Sixteen of 40 identified mutations were novel (40%). We determined 18 surface molecular defects, 10 cytosolic defects, 9 nuclear defects and 3 others. In our cohort, the most common gene was TACI (15/40 in mutation identified cases and 15/100 in all cases) followed by the others such as PLCү2, LRBA, TCF3 and STAT1. In contrast to our expectations, our results were more similar to American and European population rather than Asians, although we also have high consanguinity rates and live on the geography between Europe and Asia. Genetic investigation is a great challenge, because of the complexity and heterogenity of the disease and each country has to know their own current genetic landscape in CVID for a better and successful management of the patients. common variable immune deficiency targeted next generation sequencing whole exome sequencing INTRODUCTION Common Variable immunodeficiency (CVID) is a highly heterogeneous primary antibody deficiency with different clinical presentations and various severe complications such as autoimmune disease, enteropathy, polyclonal lymphocytic infiltration or cancer ( 1 , 2 ). With the increasing number of disease causing genes identified in CVID, it is very clear that CVID is an umbrella diagnosis and many of these genetic defects cause different disease entities ( 1 ). In 2018, it has been reported that most CVID cases have an unknown genetic cause, with monogenic diseases accounting for only 2%-10% with autosomal recessive and dominant mutations ( 3 ). Identification of the causes of monogenetic CVID has increased in the last 5 years by means of worldwide availability of appropriate genetic diagnostic methods ( 4 ). In the unique study about type of gene mutations in CVID patients, overall, 31%, 36% and 54% of the patients in the United States, Swedish and Iranian cohorts had been shown to have a molecular defect ( 5 ). In addition, recent studies demonstrated the role of epigenetic modifications in the development of CVID associated disorders ( 4 ). Gene mutations were described at three different cellular levels such as surface, cytoplasm and nucleus ( 4 ). In the study by Abolhassani et al ( 5 ), the genetic causes of CVID patients were examined in three different countries, namely United States, Sweden and Iran and the most common variations were identified in transmembrane activator and calcium modulator and cyclophilin ligand interactor ( TACI) , lypopolysaccharide-responsive beige-like anchor protein ( LRBA ) and also again LRBA genes, respectively. In this study, although some of the genes were identified in each group and country, for the majority of cases different genes were identified in each of the cohorts, illustrating different geographical areas, ethnicities and degrees of consanguinity of patients seen at these centers. Here, we describe the results of genetic analysis of 100 heterogenous Turkish children diagnosed as CVID. These analyses demonstrate the incidence and range of genes that lead to the CVID phenotype and compare them with previously performed studies from different countries and populations. We hope it will help us to understand the role of ethnicity, geographical area and consanguineous marriages. This is the first study from Turkey showing disease-causing genes for CVID. PATIENTS AND METHODS A total of 100 subjects who had been diagnosed as CVID and followed-up in Ege University, Faculty of Medicine, Department of Pediatric Immunology, Izmir, Turkey were included in the study. European Society for Immunodeficiencies (ESID) probable criteria for CVID was used for all patients. They were as follows; Male or female patient who has a marked decrease of IgG (at least 2 SD below the mean for age) and a marked decrease in at least one of the isotypes IgM or IgA, and an onset of immunodeficiency at greater than 2 years of age and absent isohemagglutinins and/or poor response to vaccines and excluded defined causes of hypogammaglobulinemia. Genetic testing: The genetic causes of immune deficiency were examined retrospectively from their old files and prospectively by using TNGS and WES technique. All of the patients had “targeted next generation sequencing (TNGS)” in order to understand molecular pathology. Sixty-five patients without identified disease-causing mutations had WES genetic examination. DNA extraction; DNA was extracted from whole blood using the QIAamp DNA Blood Mini Kit (Qiagen, Hilden, Germany). The quantity of extracted DNA was estimated using the Qubit™ dsDNA HS assay kit on the Qubit 2.0 Fluorometer (Thermo Fisher Scientific), according to manufacturer’s instructions. TNGS ; Library preparation was carried out using an Ion Chef System (Thermo Fisher Scientific, San Francisco, CA, USA) according to the manufacturer’s protocols. Barcoded libraries were generated from 10 ng of DNA per sample using an Ion AmpliSeq Chef Solutions (Thermo Fisher Scientific) and the Ion AmpliSeq™ Primary Immune Deficiency Research Panel v2. (Thermo Fisher Scientific). This panel is composed of 5241 amplicons in 264 genes. The prepared libraries were clonally amplified onto Ion Sphere Particles (ISP) using emulsion PCR in an Ion Chef System (Thermo Fisher Scientific) according to the manufacturer’s protocols. Enriched ISPs were loaded onto 530 chips accommodating 16 samples on a single chip per sequencing run. Sequencing was performed on an Ion S5 Sequencer using an Ion 530 Chip and an Ion 530 kit–Chef Kit (all from Thermo Fisher Scientific). Alignment of the sequences to reference genome hg19 and base calling were performed using the Torrent Suite software. WES; NGS (next-generation sequencing) was performed for whole-exome sequencing analysis using DNBSEQ-G400 (MGI Tech., China). KAPA HyperExome Kit (Roche) was used according to the manufacturer’s protocol. Average coverage of > 140× read depth was observed for 96% of the exome. Variant Interpretation; The clinical significance of the novel variants was examined using the standards and guidelines for the interpretation of sequence variants recommended by the American College of Medical Genetics and Genomics (ACMG Laboratory Quality Assurance Committee) and the Association for Molecular Pathology (AMP) ( 6 ). Minor Allele Frequencies were examined through access to population databases and in specific to the NCBI dbSNP build141 ( http://www.ncbi.nlm.nih.gov/SNP/ ), 1000 Genomes Project ( http://www.1000genomes.org/ ), Exome Aggregation Consortium (ExAC) ( http://exac.broadinstitute.org/ ), and Genome Aggregation Database (gnomAD) ( http://gnomad.broadinstitute.org/ ). Disease specific information for variants were retrieved from ClinVar ( https://www.ncbi.nlm.nih.gov/clinvar/ ) and OMIM ( https://www.omim.org/ ). The impact of novel variants on the protein structure was then classified using several in silico prediction tools such as GERPP, Polyphen-2, and SIFT ( 7 , 8 , 9 ). Variant pathogenicity was classified in accordance with American College of Medical Genetics (ACMG) recommendations. All novel genetic variants were screened for pathogenicity, mode of inheritance and clinical phenotypes. Finally, candidate pathogenic variants identified by NGS were verified with Sanger sequencing on ABI PRISM 3500 DNA analyzer (Applied Biosystems). Following this segregation analysis was performed. Mutations identified in CVID patients were listed in four different groups, such as surface molecular defects, cytosolic defects, nuclear defects and other gene defects. The observed mutations were classified as pathogenic, likely pathogenic and VUS according to ACMG criteria. Ethical permissions were obtained from the ethics committee and informed consent was obtained from all individuals and/or their legal guardians. RESULTS The median age of our patients was 5.8 years (range, 3.0–16.0 years) at admission and 9.0 years (range, 4.8–21.0 years) at the time of genetic diagnosis; 65 were male and 35 were female. Of these subjects 24 had consanguineous parents (24%) and 76 had non-consanguineous parents. All the CVID patients were initially examined with TNGS technique (100%) and 35 disease-causing mutations were detected (35%). The rest of patients (65 cases) had one more genetic examination such as WES and genetic backgrounds were cleared in five more cases as well as previously observed mutations in TNGS. Then, the ratio of disease-causing mutations by WES in Turkish CVID children was 40%. In other words, pathogenic mutations were exactly defined in 40% of Turkish CVID patients. A total of 17 different genes were found to be responsible for pathogenesis in our CVID patients. Sixteen of these 40 mutations were novel (40%) and 24 of them were previously described (60%) (Table-1-2-3-4). Our common variable immunodeficiency patients with surface molecular defects (n:18) were listed in Table-1. Different members of tumor necrosis factor (TNF) receptor superfamily have been found to be involved in the pathogenesis of CVID. The single gene defects in this pathway affect transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI, encoded by TNFRSF13B ), TNF-like weak inducer of apoptosis (TWEAK, April, encoded by TNFRSF12 ) and B cell activating factor belonging to the TNF family BAFF receptor (BAFF-R encoded by TNFRSF13C ). In addition to TNF receptor superfamily, defect in co-stimulatory molecules such as IL-21 receptor has been identified in our CVID patients. The most common defect both in all CVID patients (15/100) (37.5%) and in patients with surface molecular defects (15/18) (83.3%) was TNFRSF13B (TACI) (n:15). The other surface molecular defects were encoded by TNFRSF12 (n:1), TNFRSF13C (n:1) and IL-21R (n:1). All the observed TACI defects were previously described, although new mutations were identified for TWEAK and IL21R genes (Table-1). Both of the novel mutations in this group were described by means of WES. In Table-2, our common variable immunodeficiency patients with cytosolic defects (n:10) were listed. Genetic defects in some cytosolic proteins, such as phospholipase C gamma 2 ( PLCү2) which functions in B-cell receptor signaling (n:3) and LRBA which participating in vesicular trafficking and signal transduction (n:3) were observed in our CVID patients study group. Demethylation during the transition from naive to memory cells may be impaired in TCF3 (transcription factor 3) defects and we identified 3 patients with this defect in a total of 100 CVID patients (3%). In addition, hypermethylation in B cells was reported to be observed in PIK3CD (phosphatidyl inositol 3-kinase, catalytic, delta) gene defects and we found a previously described disease causing mutation in one of our patients (Table-2). Two PLCү2 , 3 LRBA and 3 TCF3 genes mutations were novel and seven of these eight novel mutations were identified by TNGS and one TCF3 mutation with WES (Table-2). Nuclear defects (n:9) which were observed in our common variable immunodeficiency patients were listed in Table-3 and they were as follows; STAT1 ( a member of transcription protein family important in many biological actions such as B cell differentiation) (n:3), NFKB2 (a signaling factor important for B cell maturation and differentiation) (n:2), TTC37 (a member of Ski complex degrading exosomal RNA) (n:1), PTEN ( downregulates AKT signaling in the mTOR pathway) (n:1), TRNT1 (a RNA polymerase important for maturation of nuclear and mitochondrial transfer RNAs) (n:1) and IKZF1 ( a hematopoietic zinc-finger transcription functioning in B-cell lymphopoiesis ) (n:1). TRNT1, IKZF1 and one STAT1 mutations were novel (Table-3). We also identified three different genetic defect causing CVID, namely PRKDC (protein kinase DNA-activated, catalytic subunit), MALT1 (mucosa associated lymphoid tissue lymphoma translocation gene 1) (novel homozygous mutation) and MAGT1 (Magnesium transporter 1) (novel hemizygous mutation) (Table-4). DISCUSSION CVID is characterized by humoral immune deficiency with onset after 2 years of age and usually in young adulthood and it is one the most common form of primary antibody disorders in humans with an estimated incidence of 1:25000 ( 20 , 21 ). In 2012, our 25 CVID patients were screened for alterations in genes known to be associated with autosomal recessive CVID and only one patient carried heterozygous TNFRSF13B c.310T > C (p. Cys104Arg) (rs34557412) (4%) which was recorded as disease causing ( 20 ). Seven of the 25 patients in that study had consanguineous parents (28%) ( 20 ). Karaca et al ( 21 ) have reported the rate of parental consanguinity in Turkish CVID patients as 19.1%. In both US and Sweden study, known consanguineous parents were 0%, while it was 63% in Iran. In this study, we have included 100 Turkish CVID patients diagnosed and followed-up with ESID criteria and found out that parental consanguinity is 24%. In summary, the rate of consanguinity for CVID patients in our reported studies differ between 19.1% and 28.0%, very high than American and Europe population and so much less than Iranian cohort. Our study subjects were recruited only from childhood population whereas their median age was 5.8 years when they were diagnosed as CVID and our genetic diagnostic delay was about 3.2 years. In Abolhassani’s study, median age of the US, Swedish and Iranian patients, were 44 years (range, 5–85 years), 49.5 years (range, 4–90 years) and 9 years (range, 1–65 years), respectively ( 5 ). This data shows us that Abolhassani et al recruited not only children CVID cases, but also adult ones. Besides geographical and ethnical facts, great differences in age groups may be one of the reasons of different findings between our study and Abolhassani’s study, because different genotypes cause different CVID phenotypes and different ages for the beginning of clinical and infectious symptoms. Another important difference between these two studies is about the gender of patients whereas in Turkish patients males were 65% (as it was expected for primary immune deficiencies) and in three countries from different continents males were 48.5% of the study population. In three different countries from America, Asia and Europe, mutations leading to CVID phenotype were identified in 31–54% of patients although this rate was less than 10% before 5–10 years ( 5 ). In our study, pathogenic mutations were defined in 40% of Turkish CVID patients living in a geographical area on the bridge between Asia and Europe. In Abolhassani’s study, 68 known disease-causing genes underlying an immune defect presenting as CVID were revealed while in our study 17 different genes and 40 pathogenic mutations were identified. Abolhassani et al ( 5 ) included X-linked agammaglobulinemia patients (Bruton tyrosine kinase- BTK ), immune dysregulation syndromes ( FOXP3, DOCK8 ), WHIM syndrome cases, X-linked hyper IgM case ( CD40L ) and severe combined immune deficiency patients (recombination activating genes, RAG1/RAG2 and DNA ligase 4, LIG4 ) in their study, although these patients do not fulfill the criteria for CVID. We did not enroll any of these patients and we found less number of different genes causing CVID. Besides previously described mutations, we identified 16 novel mutations (16%) in known disease-causing genes (Table-1-2-3-4) in patients exactly diagnosed as CVID with all clinical and laboratory findings. In our Turkish cohort, the most common gene with a surface molecular defect was TACI (15/40 in mutation identified cases and 15/100 in all cases). The second most common genes were PLCү2, LRBA, TCF3 and STAT1 , all of them were 3/40 in genetically defined cases and 3/100 in all CVID patients. NFKB2 gene was the other common one with two previously defined mutations (Table-3). We had expected that Turkish and Iranian cohorts from very near geographical area with similar median ages and with a history of consanguinity higher than 20%, would be more similar, but this was not observed as the most genes in Turkey and Iran were TACI and LRBA , respectively. TACI was the predominant gene in US identified in 35% of cases while LRBA and TACI were both the most common ones (10.8% each of them) in Sweden ( 5 ). The results of our Turkish cohort were more similar to European (Sweden) and American (US) population. The advent of TNGS has enabled rapid identification of the molecular etiology of CVID for the last 10 years. In Turkish laboratories, next-generation sequencing is highly used for genetic diagnosis of inborn errors of immunity while WES is commonly used to diagnose CVID in developed countries ( 22 ). In TNGS, gene panels are customized for specific genetic diseases, considering the high specificity and sensitivity of the entire genes with the maximum coverage because of the limited numbers of the gene in the customized panel. TNGS panel has been reported to provide a diagnosis to 80% of cases ( 23 ). TNGS revealed disease-causing mutations in 35% of our CVID patients whereas WES revealed pathogenic genes in 40% of the study population. We believe that any of the above genetic tests where they are available enable us to define the molecular defect in CVID and improves the quality of disease management and patient outcome. In conclusion, a combination of clinical and genetic diagnosis are recently more extensively used in the management of CVID patients. However, because of the complexity and heterogeneity of the disease, genetic investigation is still a great challenge. In this presented study, the rate of disease-causing mutations was 40% in Turkish CVID patients (40/100) and 16 of these 40 mutations were not previously described and will add new information to the genetic databases. The most common gene was TACI (15/40 in mutation identified cases and 15/100 in all cases) in Turkish cohort followed by PLCү2, LRBA, TCF3, STAT1 and NFKB2 genes. Our results were more similar to European and American population rather than Iranian population suggesting us that geographical factors do not highly effect genetic alterations in CVID patients. Abbreviations CVID: Common variable immunodeficiency ACMG: American College of Medical Genetics VUS: variant of unknown significance PM2: Moderate evidence of pathogenicity Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or ExAC PM1: Moderate evidence of pathogenicity Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation PP2: Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease PP3: Supporting evidence of pathogenicity Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc) BP4: Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) TNGS: Targeted Next Generation Sequencing WES: Whole Exome Sequencing Declarations Acknowledgement and partial funding : This work was partly supported by The Jeffrey Modell Foundation (JMF). The authors thank The Jeffrey Modell Foundation for their precious support. Author contributions: Ayse Aygun: Study conception, design and write the manuscript. Ezgi Topyıldız: Data collection. Necil Kutukculer, Neslihan Edeer Karaca: Analysis and interpretation of results, data collection. Mehmet Geyik: Material preparation . Asude Durmaz, Guzide Aksu, Ayca Aykut: Data collection. Necil Kutukculer: Study design, supervised the work, performed the analysis, contributed data, and analysis tools. All authors read and approved the final version of the manuscript. Availability of data and material: The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation, to any qualifed researcher. Ethics approval: The study was approved by the local ethics committee (Ege University Faculty of Medicine Clinical Ethical Board Approval No: 23-IT/33) Consent to Participate : Written informed consent was obtained from the parents or legal guardians. Consent for Publication : The authors affirm that parents or legal guardians provided informed consent for publication. Conflict of Interest: The authors declare that they have no conflict of interest. References Bogaert DJ, Dullaers M, Lambrecht BN, Vermaelen KY, De Baere E, Haerynck F. Genes associated with common variable immunodeficiency: one diagnosis to rule them all?. J Med Genet. 2016;53(9):575-90. Li J, Wei Z, Li YR, Maggadottir SM, Chang X, Desai A, Hakonarson H. Understanding the genetic and epigenetic basis of common variable immunodeficiency disorder through omics approaches. Biochim Biophys Acta. 2016;2656-63. Li R, Zheng Y, Li Y, Zhang R, Wang F, Yang D et al. 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Targeted next-generation sequencing revealed a novel homozygous mutation in the LRBA gene causes severe hemolysis associated with Inborn Errors of Immunity. Hematology 2022;27(1):441-48. Tables Table-1: Our common variable immunodeficiency patients with surface molecular defects (n:18). Patient no Gene Zygosity Variation ACMG classification Novel/ Previously described Method Reference 1 TNFRSF13B (TACI) Heterozygous c.716C>T (p.Ala239Val) VUS (PM2) Previously described TNGS 2 TNFRSF13B (TACI) Compound heterozygous c.579C>A (p.Cys193Ter) c.310T>C (p.Cys104Arg) Pathogenic Pathogenic Previously described TNGS 3 TNFRSF13B (TACI) Heterozygous c.310T>C (p.Cys104Arg) Pathogenic Previously described TNGS 10 4 TNFRSF13B (TACI) Heterozygous c.542C>A (p.Ala181Glu) Pathogenic Previously described TNGS 5 TNFRSF13B (TACI) Heterozygous c.579C>A (p.Cys193Ter) Pathogenic Previously described TNGS 6 TNFRSF13B (TACI) Heterozygous c.204dupA (p.Leu69ThrfsTer12) Pathogenic Previously described TNGS 10 7 TNFRSF13B (TACI) Heterozygous c.204dupA (p.Leu69ThrfsTer12) Pathogenic Previously described TNGS 8 TNFRSF13B (TACI) Heterozygous c.204dupA (p.Leu69ThrfsTer12) Pathogenic Previously described TNGS 9 TNFRSF13B (TACI) Heterozygous c.418G>A (p.Glu140Lys) VUS (PM2) Previously described TNGS 10 TNFRSF13B (TACI) Heterozygous c.260T>A (p.Ile87Asn) Pathogenic Previously described TNGS 11 TNFRSF13B (TACI) Heterozygous c.579C>A (p.Cys193Ter) Pathogenic Previously described TNGS 12 TNFRSF13B (TACI) Heterozygous c.515G>A (p.Cys172Tyr) VUS (PM2,PP3) Previously described TNGS 13 TNFRSF13B (TACI) Heterozygous c.204dupA (p.Leu69ThrfsTer12) Pathogenic Previously described TNGS 14 TNFRSF13B (TACI) Heterozygous c.310T>C (p.Cys104Arg) Pathogenic Previously described TNGS 15 TNFRSF13B (TACI) Heterozygous c.579C>A (p.Cys193Ter) Pathogenic Previously described TNGS 16 TNFRSF25 (Tweak)(April) Heterozygous c.868G>A (p.Glu290Lys) VUS (PM2) Novel WES 17 TNFRSF13C (BAFF-R) Homozygous c.347C>T (p.Ala116Val) VUS(PM2,BP4) Previously described TNGS 18 IL21R Homozygous c.132delC (p.Ser45fs) Likely Pathogenic Novel WES 11 Table-2: Our common variable immunodeficiency patients with cytosolic defects (n:10). Patient no Gene Zygosity Variation ACMG classification Novel/ Previously described Method Reference 1 PLCү2 Heterozygous c.2152A>C (p.Ser718Arg) VUS (PM2) Novel TNGS 12 2 PLCү2 Heterozygous c.502A>G (p.Thr168Ala) VUS (PM2,BP4) Previously described TNGS 12 3 PLCү2 Heterozygous c.1760G>A (p.Arg587Gln) VUS (PM2) Novel TNGS 12 4 PIK3CD Heterozygous c.401C>T (p.Pro134Leu) VUS (PM2,PP2) Previously described TNGS 5 LRBA Homozygous c.2496C>A (p.Cys832Ter) Likely Pathogenic Novel TNGS 13 6 LRBA Homozygous c.2496C>A (p.Cys832Ter) Likely Pathogenic Novel TNGS 13 7 LRBA Homozygous c.2447del p.(Pro816Leufs4) Likely Pathogenic Novel TNGS 14 8 TCF3 Heterozygous c.145+7C>A VUS (PM2,BP4) Novel WES 9 TCF3 Homozygous c.1643G>A (p.Arg548His) VUS (PM2,PP3) Novel TNGS 10 TCF3 Heterozygous, c.511 A>G (p.Lys171Glu) Likely Pathogenic Novel TNGS Table-3:Our common variable immunodeficiency patients with nuclear defects (n:9) Patient no Gene Zygosity Variation ACMG classification Novel/ Previously described Method Rererence 1 STAT1 Heterozygous c.295A>G (p.Ile99Val) VUS (PM2,PP2,BP4) Novel TNGS 2 STAT1 Heterozygous c.1154 C>T (p.Thr385Met) Pathogenic Previously described TNGS 15 3 STAT1 Heterozygous c.1154 C>T (p.Thr385Met) Pathogenic Previously described TNGS 4 TTC37 Homozygous c.2210T>C (p.Val737Ala) VUS (PM2) Novel TNGS 16 5 PTEN Heterozygous c.389 G>C (p.Arg130Pro) Pathogenic Previously described WES 17 6 TRNT1 Homozygous, c.914A>T (p.Asp305Val) VUS (PM2) Novel TNGS 18 7 IKZF1 Heterozygous c.488A>C (p.His163Pro) Likely Pathogenic Novel TNGS 8 NFKB2 Heterozygous c.2557C>T (p.Arg853Ter) Pathogenic Previously described TNGS 9 NFKB2 Heterozygous c.2557C>T (p.Arg853Ter) Pathogenic Previously described WES Table-4: Our common variable immunodeficiency patients with other defects (n: 3) Patient no Gene Zygosity Variation ACMG classification Novel/ Previously described Method 1 PRKDC Homozygous c.10143C>G (p.Phe3381Leu) VUS (PM2) Previously described TNGS 2 MALT1 Homozygous c.2418G>C (p.Glu806Asp) VUS (PM2,BP4) Novel TNGS 19 3 MAGT1 Hemizygous c.340C>T (p.Gln114Ter) Likely Pathogenic Novel TNGS Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3093761","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":213171039,"identity":"576a0ade-fbe7-48ce-9654-c1ac12df1063","order_by":0,"name":"Ayse Aygun","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ayse","middleName":"","lastName":"Aygun","suffix":""},{"id":213171040,"identity":"ef402308-a281-4731-ade1-e76d75830e2a","order_by":1,"name":"Ezgi Topyıldız","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ezgi","middleName":"","lastName":"Topyıldız","suffix":""},{"id":213171041,"identity":"c95d3ee0-d3f0-45d7-856a-c22760a81d90","order_by":2,"name":"Mehmet Geyik","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Mehmet","middleName":"","lastName":"Geyik","suffix":""},{"id":213171042,"identity":"2997c351-0cbe-410c-bc9f-889bc4a06d5b","order_by":3,"name":"Neslihan Edeer Karaca","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Neslihan","middleName":"Edeer","lastName":"Karaca","suffix":""},{"id":213171043,"identity":"6aa0513c-aebd-4f1e-a0c6-246427664e2e","order_by":4,"name":"Asude Durmaz","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Asude","middleName":"","lastName":"Durmaz","suffix":""},{"id":213171044,"identity":"f9503728-8363-4647-82a0-bc248283bd62","order_by":5,"name":"Guzide Aksu","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Guzide","middleName":"","lastName":"Aksu","suffix":""},{"id":213171045,"identity":"537f1ee6-21e0-49c7-b684-8d0edae53c12","order_by":6,"name":"Ayca Aykut","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ayca","middleName":"","lastName":"Aykut","suffix":""},{"id":213171046,"identity":"e68dacd8-c57d-4933-8606-8f991584c194","order_by":7,"name":"Necil Kutukculer","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABEklEQVRIie3Sv0rEMBzA8V8ptEvg1hxy+Ao/KSjHic/SUEiXgoJLhxsKQrv0uBc48C1cLRTSJYtbN3sITh0CLk5q/HNCIVTdhMsXSmjph/wCAbDZ/mlVB6FePP1cAEw+P7rjJNSEfBAEmGY74o2YAcHqB3LiX231LpzdUs6eCJ6eB01x10G6YNnhqjOReSlQk4SVlNcHBPn8RspLBBmzzPPRRLBN3s+SahLnLsEaj9uEUyevNTFPhvf9gLxicN3Hz87LCGkJ7AYTmlSI1BfgZCNEcn0W5EEpH6PpBiOkMnFpKOIg97iZNPWDUmk0Kwp+pPr0DCdFs1VquZitXWEkX3DwRvD7Nvw2v/vDzzabzbYHvQHnFV3cO+uW2gAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-9196-3819","institution":"Ege University Medicine School","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Necil","middleName":"","lastName":"Kutukculer","suffix":""}],"badges":[],"createdAt":"2023-06-21 20:43:27","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3093761/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3093761/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":40976408,"identity":"4b0a3718-a430-4d96-b9e5-26782c30f03c","added_by":"auto","created_at":"2023-08-02 19:36:46","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":251560,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3093761/v1/3f4df788-049b-484a-a097-2858a0605227.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003eCurrent Genetic Defects in Common Variable Immune Deficiency Patients on the Geography Between Europe and Asia\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eCommon Variable immunodeficiency (CVID) is a highly heterogeneous primary antibody deficiency with different clinical presentations and various severe complications such as autoimmune disease, enteropathy, polyclonal lymphocytic infiltration or cancer (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). With the increasing number of disease causing genes identified in CVID, it is very clear that CVID is an umbrella diagnosis and many of these genetic defects cause different disease entities (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn 2018, it has been reported that most CVID cases have an unknown genetic cause, with monogenic diseases accounting for only 2%-10% with autosomal recessive and dominant mutations (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Identification of the causes of monogenetic CVID has increased in the last 5 years by means of worldwide availability of appropriate genetic diagnostic methods (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). In the unique study about type of gene mutations in CVID patients, overall, 31%, 36% and 54% of the patients in the United States, Swedish and Iranian cohorts had been shown to have a molecular defect (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn addition, recent studies demonstrated the role of epigenetic modifications in the development of CVID associated disorders (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Gene mutations were described at three different cellular levels such as surface, cytoplasm and nucleus (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). In the study by Abolhassani et al (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e), the genetic causes of CVID patients were examined in three different countries, namely United States, Sweden and Iran and the most common variations were identified in transmembrane activator and calcium modulator and cyclophilin ligand interactor (\u003cem\u003eTACI)\u003c/em\u003e, lypopolysaccharide-responsive beige-like anchor protein (\u003cem\u003eLRBA\u003c/em\u003e) and also again \u003cem\u003eLRBA\u003c/em\u003e genes, respectively. In this study, although some of the genes were identified in each group and country, for the majority of cases different genes were identified in each of the cohorts, illustrating different geographical areas, ethnicities and degrees of consanguinity of patients seen at these centers.\u003c/p\u003e \u003cp\u003eHere, we describe the results of genetic analysis of 100 heterogenous Turkish children diagnosed as CVID. These analyses demonstrate the incidence and range of genes that lead to the CVID phenotype and compare them with previously performed studies from different countries and populations. We hope it will help us to understand the role of ethnicity, geographical area and consanguineous marriages. This is the first study from Turkey showing disease-causing genes for CVID.\u003c/p\u003e"},{"header":"PATIENTS AND METHODS","content":" \u003cp\u003e A total of 100 subjects who had been diagnosed as CVID and followed-up in Ege University, Faculty of Medicine, Department of Pediatric Immunology, Izmir, Turkey were included in the study. European Society for Immunodeficiencies (ESID) probable criteria for CVID was used for all patients. They were as follows; Male or female patient who has a marked decrease of IgG (at least 2 SD below the mean for age) and a marked decrease in at least one of the isotypes IgM or IgA, and an onset of immunodeficiency at greater than 2 years of age and absent isohemagglutinins and/or poor response to vaccines and excluded defined causes of hypogammaglobulinemia.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eGenetic testing:\u003c/h2\u003e \u003cp\u003eThe genetic causes of immune deficiency were examined retrospectively from their old files and prospectively by using TNGS and WES technique.\u003c/p\u003e \u003cp\u003eAll of the patients had \u0026ldquo;targeted next generation sequencing (TNGS)\u0026rdquo; in order to understand molecular pathology. Sixty-five patients without identified disease-causing mutations had WES genetic examination.\u003c/p\u003e \u003cp\u003e \u003cb\u003eDNA extraction;\u003c/b\u003e DNA was extracted from whole blood using the QIAamp DNA Blood Mini Kit (Qiagen, Hilden, Germany). The quantity of extracted DNA was estimated using the Qubit\u0026trade; dsDNA HS assay kit on the Qubit 2.0 Fluorometer (Thermo Fisher Scientific), according to manufacturer\u0026rsquo;s instructions.\u003c/p\u003e \u003cp\u003e \u003cb\u003eTNGS\u003c/b\u003e; Library preparation was carried out using an Ion Chef System (Thermo Fisher Scientific, San Francisco, CA, USA) according to the manufacturer\u0026rsquo;s protocols. Barcoded libraries were generated from 10 ng of DNA per sample using an Ion AmpliSeq Chef Solutions (Thermo Fisher Scientific) and the Ion AmpliSeq\u0026trade; Primary Immune Deficiency Research Panel v2. (Thermo Fisher Scientific). This panel is composed of 5241 amplicons in 264 genes. The prepared libraries were clonally amplified onto Ion Sphere Particles (ISP) using emulsion PCR in an Ion Chef System (Thermo Fisher Scientific) according to the manufacturer\u0026rsquo;s protocols. Enriched ISPs were loaded onto 530 chips accommodating 16 samples on a single chip per sequencing run. Sequencing was performed on an Ion S5 Sequencer using an Ion 530 Chip and an Ion 530 kit\u0026ndash;Chef Kit (all from Thermo Fisher Scientific). Alignment of the sequences to reference genome hg19 and base calling were performed using the Torrent Suite software.\u003c/p\u003e \u003cp\u003e \u003cb\u003eWES;\u003c/b\u003e NGS (next-generation sequencing) was performed for whole-exome sequencing analysis using DNBSEQ-G400 (MGI Tech., China). KAPA HyperExome Kit (Roche) was used according to the manufacturer\u0026rsquo;s protocol. Average coverage of \u0026gt;\u0026thinsp;140\u0026times; read depth was observed for 96% of the exome.\u003c/p\u003e \u003cp\u003e\u003cb\u003eVariant Interpretation;\u003c/b\u003e The clinical significance of the novel variants was examined using the standards and guidelines for the interpretation of sequence variants recommended by the American College of Medical Genetics and Genomics (ACMG Laboratory Quality Assurance Committee) and the Association for Molecular Pathology (AMP) (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Minor Allele Frequencies were examined through access to population databases and in specific to the NCBI dbSNP build141 (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.ncbi.nlm.nih.gov/SNP/\u003c/span\u003e\u003cspan address=\"http://www.ncbi.nlm.nih.gov/SNP/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), 1000 Genomes Project (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.1000genomes.org/\u003c/span\u003e\u003cspan address=\"http://www.1000genomes.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), Exome Aggregation Consortium (ExAC) (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://exac.broadinstitute.org/\u003c/span\u003e\u003cspan address=\"http://exac.broadinstitute.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), and Genome Aggregation Database (gnomAD) (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://gnomad.broadinstitute.org/\u003c/span\u003e\u003cspan address=\"http://gnomad.broadinstitute.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). Disease specific information for variants were retrieved from ClinVar (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/clinvar/\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/clinvar/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) and OMIM (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.omim.org/\u003c/span\u003e\u003cspan address=\"https://www.omim.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). The impact of novel variants on the protein structure was then classified using several in silico prediction tools such as GERPP, Polyphen-2, and SIFT (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Variant pathogenicity was classified in accordance with American College of Medical Genetics (ACMG) recommendations. All novel genetic variants were screened for pathogenicity, mode of inheritance and clinical phenotypes. Finally, candidate pathogenic variants identified by NGS were verified with Sanger sequencing on ABI PRISM 3500 DNA analyzer (Applied Biosystems). Following this segregation analysis was performed.\u003c/p\u003e \u003cp\u003eMutations identified in CVID patients were listed in four different groups, such as surface molecular defects, cytosolic defects, nuclear defects and other gene defects. The observed mutations were classified as pathogenic, likely pathogenic and VUS according to ACMG criteria.\u003c/p\u003e \u003cp\u003e Ethical permissions were obtained from the ethics committee and informed consent was obtained from all individuals and/or their legal guardians.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003eThe median age of our patients was 5.8 years (range, 3.0\u0026ndash;16.0 years) at admission and 9.0 years (range, 4.8\u0026ndash;21.0 years) at the time of genetic diagnosis; 65 were male and 35 were female. Of these subjects 24 had consanguineous parents (24%) and 76 had non-consanguineous parents.\u003c/p\u003e \u003cp\u003eAll the CVID patients were initially examined with TNGS technique (100%) and 35 disease-causing mutations were detected (35%).\u003c/p\u003e \u003cp\u003eThe rest of patients (65 cases) had one more genetic examination such as WES and genetic backgrounds were cleared in five more cases as well as previously observed mutations in TNGS. Then, the ratio of disease-causing mutations by WES in Turkish CVID children was 40%. In other words, pathogenic mutations were exactly defined in 40% of Turkish CVID patients. A total of 17 different genes were found to be responsible for pathogenesis in our CVID patients.\u003c/p\u003e \u003cp\u003eSixteen of these 40 mutations were novel (40%) and 24 of them were previously described (60%) (Table-1-2-3-4).\u003c/p\u003e \u003cp\u003eOur common variable immunodeficiency patients with surface molecular defects (n:18) were listed in Table-1. Different members of tumor necrosis factor (TNF) receptor superfamily have been found to be involved in the pathogenesis of CVID. The single gene defects in this pathway affect transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI, encoded by \u003cem\u003eTNFRSF13B\u003c/em\u003e), TNF-like weak inducer of apoptosis (TWEAK, April, encoded by \u003cem\u003eTNFRSF12\u003c/em\u003e) and B cell activating factor belonging to the TNF family BAFF receptor (BAFF-R encoded by \u003cem\u003eTNFRSF13C\u003c/em\u003e). In addition to TNF receptor superfamily, defect in co-stimulatory molecules such as IL-21 receptor has been identified in our CVID patients. The most common defect both in all CVID patients (15/100) (37.5%) and in patients with surface molecular defects (15/18) (83.3%) was \u003cem\u003eTNFRSF13B (TACI)\u003c/em\u003e (n:15). The other surface molecular defects were encoded by \u003cem\u003eTNFRSF12\u003c/em\u003e (n:1), \u003cem\u003eTNFRSF13C\u003c/em\u003e (n:1) and \u003cem\u003eIL-21R\u003c/em\u003e (n:1). All the observed TACI defects were previously described, although new mutations were identified for \u003cem\u003eTWEAK\u003c/em\u003e and \u003cem\u003eIL21R\u003c/em\u003e genes (Table-1). Both of the novel mutations in this group were described by means of WES.\u003c/p\u003e \u003cp\u003eIn Table-2, our common variable immunodeficiency patients with cytosolic defects (n:10) were listed. Genetic defects in some cytosolic proteins, such as phospholipase C gamma 2 (\u003cem\u003ePLCү2)\u003c/em\u003e which functions in B-cell receptor signaling (n:3) and \u003cem\u003eLRBA\u003c/em\u003e which participating in vesicular trafficking and signal transduction (n:3) were observed in our CVID patients study group. Demethylation during the transition from naive to memory cells may be impaired in \u003cem\u003eTCF3\u003c/em\u003e (transcription factor 3) defects and we identified 3 patients with this defect in a total of 100 CVID patients (3%). In addition, hypermethylation in B cells was reported to be observed in \u003cem\u003ePIK3CD\u003c/em\u003e (phosphatidyl inositol 3-kinase, catalytic, delta) gene defects and we found a previously described disease causing mutation in one of our patients (Table-2). Two \u003cem\u003ePLCү2\u003c/em\u003e, 3 \u003cem\u003eLRBA\u003c/em\u003e and 3 \u003cem\u003eTCF3\u003c/em\u003e genes mutations were novel and seven of these eight novel mutations were identified by TNGS and one \u003cem\u003eTCF3\u003c/em\u003e mutation with WES (Table-2).\u003c/p\u003e \u003cp\u003eNuclear defects (n:9) which were observed in our common variable immunodeficiency patients were listed in Table-3 and they were as follows; \u003cem\u003eSTAT1\u003c/em\u003e ( a member of transcription protein family important in many biological actions such as B cell differentiation) (n:3), \u003cem\u003eNFKB2\u003c/em\u003e (a signaling factor important for B cell maturation and differentiation) (n:2), \u003cem\u003eTTC37\u003c/em\u003e (a member of Ski complex degrading exosomal RNA) (n:1), \u003cem\u003ePTEN\u003c/em\u003e ( downregulates AKT signaling in the mTOR pathway) (n:1), \u003cem\u003eTRNT1\u003c/em\u003e (a RNA polymerase important for maturation of nuclear and mitochondrial transfer RNAs) (n:1) and \u003cem\u003eIKZF1\u003c/em\u003e ( a hematopoietic zinc-finger transcription functioning in B-cell lymphopoiesis ) (n:1). \u003cem\u003eTRNT1, IKZF1\u003c/em\u003e and one \u003cem\u003eSTAT1\u003c/em\u003e mutations were novel (Table-3).\u003c/p\u003e \u003cp\u003eWe also identified three different genetic defect causing CVID, namely \u003cem\u003ePRKDC\u003c/em\u003e (protein kinase DNA-activated, catalytic subunit), \u003cem\u003eMALT1\u003c/em\u003e (mucosa associated lymphoid tissue lymphoma translocation gene 1) (novel homozygous mutation) and \u003cem\u003eMAGT1\u003c/em\u003e (Magnesium transporter 1) (novel hemizygous mutation) (Table-4).\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eCVID is characterized by humoral immune deficiency with onset after 2 years of age and usually in young adulthood and it is one the most common form of primary antibody disorders in humans with an estimated incidence of 1:25000 (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). In 2012, our 25 CVID patients were screened for alterations in genes known to be associated with autosomal recessive CVID and only one patient carried heterozygous \u003cem\u003eTNFRSF13B\u003c/em\u003e c.310T\u0026thinsp;\u0026gt;\u0026thinsp;C (p. Cys104Arg) (rs34557412) (4%) which was recorded as disease causing (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Seven of the 25 patients in that study had consanguineous parents (28%) (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Karaca et al (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e) have reported the rate of parental consanguinity in Turkish CVID patients as 19.1%. In both US and Sweden study, known consanguineous parents were 0%, while it was 63% in Iran. In this study, we have included 100 Turkish CVID patients diagnosed and followed-up with ESID criteria and found out that parental consanguinity is 24%. In summary, the rate of consanguinity for CVID patients in our reported studies differ between 19.1% and 28.0%, very high than American and Europe population and so much less than Iranian cohort.\u003c/p\u003e \u003cp\u003eOur study subjects were recruited only from childhood population whereas their median age was 5.8 years when they were diagnosed as CVID and our genetic diagnostic delay was about 3.2 years. In Abolhassani\u0026rsquo;s study, median age of the US, Swedish and Iranian patients, were 44 years (range, 5\u0026ndash;85 years), 49.5 years (range, 4\u0026ndash;90 years) and 9 years (range, 1\u0026ndash;65 years), respectively (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). This data shows us that Abolhassani et al recruited not only children CVID cases, but also adult ones. Besides geographical and ethnical facts, great differences in age groups may be one of the reasons of different findings between our study and Abolhassani\u0026rsquo;s study, because different genotypes cause different CVID phenotypes and different ages for the beginning of clinical and infectious symptoms. Another important difference between these two studies is about the gender of patients whereas in Turkish patients males were 65% (as it was expected for primary immune deficiencies) and in three countries from different continents males were 48.5% of the study population.\u003c/p\u003e \u003cp\u003eIn three different countries from America, Asia and Europe, mutations leading to CVID phenotype were identified in 31\u0026ndash;54% of patients although this rate was less than 10% before 5\u0026ndash;10 years (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). In our study, pathogenic mutations were defined in 40% of Turkish CVID patients living in a geographical area on the bridge between Asia and Europe. In Abolhassani\u0026rsquo;s study, 68 known disease-causing genes underlying an immune defect presenting as CVID were revealed while in our study 17 different genes and 40 pathogenic mutations were identified. Abolhassani et al (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) included X-linked agammaglobulinemia patients (Bruton tyrosine kinase-\u003cem\u003eBTK\u003c/em\u003e), immune dysregulation syndromes (\u003cem\u003eFOXP3, DOCK8\u003c/em\u003e), WHIM syndrome cases, X-linked hyper IgM case (\u003cem\u003eCD40L\u003c/em\u003e) and severe combined immune deficiency patients (recombination activating genes, \u003cem\u003eRAG1/RAG2\u003c/em\u003e and DNA ligase 4, \u003cem\u003eLIG4\u003c/em\u003e) in their study, although these patients do not fulfill the criteria for CVID. We did not enroll any of these patients and we found less number of different genes causing CVID. Besides previously described mutations, we identified 16 novel mutations (16%) in known disease-causing genes (Table-1-2-3-4) in patients exactly diagnosed as CVID with all clinical and laboratory findings.\u003c/p\u003e \u003cp\u003eIn our Turkish cohort, the most common gene with a surface molecular defect was \u003cem\u003eTACI\u003c/em\u003e (15/40 in mutation identified cases and 15/100 in all cases). The second most common genes were \u003cem\u003ePLCү2, LRBA, TCF3\u003c/em\u003e and \u003cem\u003eSTAT1\u003c/em\u003e, all of them were 3/40 in genetically defined cases and 3/100 in all CVID patients. \u003cem\u003eNFKB2\u003c/em\u003e gene was the other common one with two previously defined mutations (Table-3). We had expected that Turkish and Iranian cohorts from very near geographical area with similar median ages and with a history of consanguinity higher than 20%, would be more similar, but this was not observed as the most genes in Turkey and Iran were \u003cem\u003eTACI\u003c/em\u003e and \u003cem\u003eLRBA\u003c/em\u003e, respectively. \u003cem\u003eTACI\u003c/em\u003e was the predominant gene in US identified in 35% of cases while \u003cem\u003eLRBA\u003c/em\u003e and \u003cem\u003eTACI\u003c/em\u003e were both the most common ones (10.8% each of them) in Sweden (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). The results of our Turkish cohort were more similar to European (Sweden) and American (US) population.\u003c/p\u003e \u003cp\u003eThe advent of TNGS has enabled rapid identification of the molecular etiology of CVID for the last 10 years. In Turkish laboratories, next-generation sequencing is highly used for genetic diagnosis of inborn errors of immunity while WES is commonly used to diagnose CVID in developed countries (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). In TNGS, gene panels are customized for specific genetic diseases, considering the high specificity and sensitivity of the entire genes with the maximum coverage because of the limited numbers of the gene in the customized panel. TNGS panel has been reported to provide a diagnosis to 80% of cases (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). TNGS revealed disease-causing mutations in 35% of our CVID patients whereas WES revealed pathogenic genes in 40% of the study population. We believe that any of the above genetic tests where they are available enable us to define the molecular defect in CVID and improves the quality of disease management and patient outcome.\u003c/p\u003e \u003cp\u003eIn conclusion, a combination of clinical and genetic diagnosis are recently more extensively used in the management of CVID patients. However, because of the complexity and heterogeneity of the disease, genetic investigation is still a great challenge. In this presented study, the rate of disease-causing mutations was 40% in Turkish CVID patients (40/100) and 16 of these 40 mutations were not previously described and will add new information to the genetic databases. The most common gene was \u003cem\u003eTACI\u003c/em\u003e (15/40 in mutation identified cases and 15/100 in all cases) in Turkish cohort followed by \u003cem\u003ePLCү2, LRBA, TCF3, STAT1\u003c/em\u003e and \u003cem\u003eNFKB2\u003c/em\u003e genes. Our results were more similar to European and American population rather than Iranian population suggesting us that geographical factors do not highly effect genetic alterations in CVID patients.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e\u003cstrong\u003eCVID:\u0026nbsp;\u003c/strong\u003eCommon variable immunodeficiency\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eACMG:\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eAmerican College of Medical Genetics\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eVUS:\u0026nbsp;\u003c/strong\u003evariant of unknown significance\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePM2:\u003c/strong\u003e Moderate evidence of pathogenicity Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or ExAC\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePM1:\u003c/strong\u003e Moderate evidence of pathogenicity Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePP2:\u0026nbsp;\u003c/strong\u003eMissense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePP3:\u003c/strong\u003e Supporting evidence of pathogenicity Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBP4:\u0026nbsp;\u003c/strong\u003eMultiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTNGS:\u0026nbsp;\u003c/strong\u003eTargeted Next Generation Sequencing\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWES:\u0026nbsp;\u003c/strong\u003eWhole Exome Sequencing\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgement and partial funding\u003c/strong\u003e: This work was partly supported by The Jeffrey Modell Foundation (JMF). The authors thank The Jeffrey Modell Foundation for their precious support.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eAuthor contributions:\u0026nbsp;\u003c/strong\u003e\u003c/em\u003eAyse Aygun: Study conception, design and write the manuscript. Ezgi Topyıldız: Data collection. Necil Kutukculer, Neslihan Edeer Karaca: Analysis and interpretation of results, data collection. Mehmet Geyik: \u003cem\u003eMaterial preparation\u003c/em\u003e. Asude Durmaz, Guzide Aksu, Ayca Aykut: Data collection. Necil Kutukculer: Study design, supervised the work, performed the analysis, contributed data, and analysis tools. \u0026nbsp; All authors read and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material:\u0026nbsp;\u003c/strong\u003eThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation, to any qualifed researcher.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval:\u0026nbsp;\u003c/strong\u003eThe study was approved by the local ethics committee (Ege University Faculty of Medicine Clinical Ethical Board Approval No: 23-IT/33)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to Participate\u003c/strong\u003e: Written informed consent was obtained from the parents or legal guardians.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for Publication\u003c/strong\u003e: The authors affirm that parents or legal guardians provided informed consent for publication.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest:\u0026nbsp;\u003c/strong\u003eThe authors declare that they have no conflict of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBogaert DJ, Dullaers M, Lambrecht BN, Vermaelen KY, De Baere E, Haerynck F. Genes associated with common variable immunodeficiency: one diagnosis to rule them all?. J Med\u003cem\u003e \u003c/em\u003eGenet. 2016;53(9):575-90.\u003c/li\u003e\n\u003cli\u003eLi J, Wei Z, Li YR, Maggadottir SM, Chang X, Desai A, Hakonarson H. Understanding the genetic and epigenetic basis of common variable immunodeficiency disorder through omics approaches. Biochim Biophys Acta. 2016;2656-63.\u003c/li\u003e\n\u003cli\u003eLi R, Zheng Y, Li Y, Zhang R, Wang F, Yang D et al. Common variable immunodeficiency with genetic defects identified by whole exome sequencing. Biomed Research International 2018;2018:3724630. \u003c/li\u003e\n\u003cli\u003eYazdani R, Habibi S, Sharifi L, Azizi G, Abolhassani H, Olbrich P, Aghamohammadi A. Common variable immunodeficiency: Epidemiology, pathogenesis, clinical manifestations, diagnosis, classification and management. J Investig Allergol Clin Immunol 2020;30:14-34.\u003c/li\u003e\n\u003cli\u003eAbolhassani H, Hammarstrom L, Cunningha-Rundles C. Current genetic landscape in common variable immune deficiency. Blood. 2020;135:656-67.\u003c/li\u003e\n\u003cli\u003eRichards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17:405\u0026ndash;24. \u003c/li\u003e\n\u003cli\u003eDavydov EV, Goode DL, Sirota M, Cooper GM, Sidow A, Batzoglou S. Identifying a high fraction of the human genome to be under selective constraint using GERP++. PLoS Computational Biology 2010;6(12):e1001025.\u003c/li\u003e\n\u003cli\u003eAdzhubei I, Jordan DM, Sunyaev SR. Predicting Functional Effect of Human Missense Mutations Using PolyPhen-2. Curr Protoc Hum Genet 2013;Chapter 7:Unit7.20.\u003c/li\u003e\n\u003cli\u003eKumar P, Henikoff S, Ng PC. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc. 2009;4(7):1073-81.\u003c/li\u003e\n\u003cli\u003eKaraca NE, Severcan EU, Guven B, Azarsiz E, Aksu G, Kutukculer N. \u003cem\u003eTNFRSF13B\u003c/em\u003e\u003cem\u003e/ TACI \u003c/em\u003e Alterations in Turkish Patients with Common Variable Immunodeficiency and IgA Deficiency.Avicenna J Med Biotechnol\u003cstrong\u003e.\u003c/strong\u003e 2018;10(3):192-95\u003c/li\u003e\n\u003cli\u003eEdeer Karaca N, \u0026Ouml;zek G, Ataseven E, T\u0026ouml;kmeci N, Şenol HD, Kıran E et al. Combined immunodeficiency with marginal zone lymphoma due to a novel homozygous mutation in \u003cem\u003eIL-21R\u003c/em\u003e gene and successful treatment with hematopoietic stem cell transplantation. Pediatr Hematol Oncol 2021;38(8):745-52\u003c/li\u003e\n\u003cli\u003eKutukculer N, Topyildiz E, Berdeli A, Guven Bilgin B, Aykut A, Durmaz A, Cogulu O et al. Four diseases, PLAID, APLAID, FCAS3 and CVID and one gene (PHOSPHOLIPASE C, GAMMA-2; \u003cem\u003ePLCG2\u003c/em\u003e): Striking clinical phenotypic overlap and difference. Clin Case Rep. 2021;9(4):2023-31. \u003c/li\u003e\n\u003cli\u003eEren Akarcan S, Edeer Karaca N, Aksu G, Aykut A, Yilmaz Karapinar D, Cetin F et al. Two male siblings with a novel \u003cem\u003eLRBA\u003c/em\u003e mutation presenting with different findings of IPEX syndrome. JMM Case Rep. 2018;5(10):e005167.\u003c/li\u003e\n\u003cli\u003eJamee M, Azizi G, Baris S, Karakoc-Aydiner E, Ozen A, Kili\u0026ccedil; SŞ et al. Clinical, immunological, molecular and therapeutic findings in monogenic immune dysregulation diseases: Middle East and North Africa registry. J Clin Immunol 2022;244:109131. \u003c/li\u003e\n\u003cli\u003eEren Akarcan S, Ulusoy Severcan E, Edeer Karaca N, Isik E, Aksu G, Migaud M et al. 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A Novel Homozygous TRNT1 Mutation in a Child with an Early Diagnosis of Common Variable Immunodeficiency Leading to Mild Hypogammaglobulinemia and Hemolytic Anemia. J Pediatr Hematol Oncol 2021;43(6):e780-84.\u003c/li\u003e\n\u003cli\u003eKutukculer N, Seeholzer T, O\u0026apos;Neill TJ, Gra\u0026szlig; C, Aykut A, Karaca NE, Durmaz A, Cogulu O, Aksu G, Gehring T, Gewies A, Krappmann D Human immune disorder associated with homozygous hypomorphic mutation affecting MALT1B splice variant. J Allergy Clin Immunol. 2021;147:775-78.e8. \u003c/li\u003e\n\u003cli\u003eKutukculer N, Gulez N, Karaca NE, Aksu G, Berdeli A. Three different classifications, B lymphocyte subpopulations, TNFRSF13B (TACI), TNFRSF13C (BAFF-R), TNFRSF13 (APRIL) gene mutations, CTLA-4 and ICOS gene polymorphisms, in Turkish patients with common variable immunodeficiency. J Clin Immunol. 2012;32(6):1165-79.\u003c/li\u003e\n\u003cli\u003eKaraca NE, Severcan EU, Bilgin BG, Azarsiz E, Akarcan S, Gunaydın NC et al. Familial inheritance and screening of first-degree relatives in common variable immunodeficiency and immunoglobulin A deficiency patients. Int J Immunopathol Pharmacol. 2018;32:2058738418779458. \u003c/li\u003e\n\u003cli\u003eMaffucci P, Filion CA, Boisson B, Itan Y, Shang L, Casanova JL et al. Genetic diagnosis using whole exome sequencing in common variable immunodeficiency. Front Immunology 2016;7:220.\u003c/li\u003e\n\u003cli\u003eKedar P, Dongerdiye R, Chandrakala S, Bargir UA, Madkaikar M. Targeted next-generation sequencing revealed a novel homozygous mutation in the LRBA gene causes severe hemolysis associated with Inborn Errors of Immunity. Hematology 2022;27(1):441-48.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable-1: Our common variable immunodeficiency patients with surface molecular defects (n:18).\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"907\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.953642384105961%\" valign=\"top\"\u003e\n \u003cp\u003ePatient no\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.35540838852097%\" valign=\"top\"\u003e\n \u003cp\u003eGene\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.368653421633555%\" valign=\"top\"\u003e\n \u003cp\u003eZygosity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.379690949227374%\" valign=\"top\"\u003e\n \u003cp\u003eVariation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.472406181015453%\" valign=\"top\"\u003e\n \u003cp\u003eACMG classification\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.2317880794702%\" valign=\"top\"\u003e\n \u003cp\u003eNovel/\u003c/p\u003e\n \u003cp\u003ePreviously described\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.161147902869757%\" valign=\"top\"\u003e\n \u003cp\u003eMethod\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.077262693156733%\" valign=\"top\"\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.953642384105961%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.35540838852097%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eTNFRSF13B\u003c/em\u003e (TACI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.368653421633555%\" valign=\"top\"\u003e\n \u003cp\u003eHeterozygous\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.379690949227374%\" valign=\"top\"\u003e\n \u003cp\u003ec.716C\u0026gt;T (p.Ala239Val)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.472406181015453%\" valign=\"top\"\u003e\n \u003cp\u003eVUS (PM2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.2317880794702%\" valign=\"top\"\u003e\n \u003cp\u003ePreviously described\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.161147902869757%\" valign=\"top\"\u003e\n \u003cp\u003eTNGS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.077262693156733%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.953642384105961%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.35540838852097%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eTNFRSF13B\u003c/em\u003e (TACI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.368653421633555%\" valign=\"top\"\u003e\n \u003cp\u003eCompound heterozygous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.379690949227374%\" valign=\"top\"\u003e\n \u003cp\u003ec.579C\u0026gt;A (p.Cys193Ter)\u003c/p\u003e\n \u003cp\u003ec.310T\u0026gt;C (p.Cys104Arg)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.472406181015453%\" valign=\"top\"\u003e\n \u003cp\u003ePathogenic\u003c/p\u003e\n \u003cp\u003ePathogenic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.2317880794702%\" valign=\"top\"\u003e\n \u003cp\u003ePreviously described\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.161147902869757%\" valign=\"top\"\u003e\n \u003cp\u003eTNGS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.077262693156733%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.953642384105961%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.35540838852097%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eTNFRSF13B\u003c/em\u003e (TACI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.368653421633555%\" valign=\"top\"\u003e\n \u003cp\u003eHeterozygous\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.379690949227374%\" valign=\"top\"\u003e\n \u003cp\u003ec.310T\u0026gt;C (p.Cys104Arg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.472406181015453%\" valign=\"top\"\u003e\n \u003cp\u003ePathogenic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.2317880794702%\" valign=\"top\"\u003e\n \u003cp\u003ePreviously described\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.161147902869757%\" valign=\"top\"\u003e\n \u003cp\u003eTNGS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.077262693156733%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.953642384105961%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.35540838852097%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eTNFRSF13B\u003c/em\u003e (TACI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.368653421633555%\" valign=\"top\"\u003e\n \u003cp\u003eHeterozygous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.379690949227374%\" valign=\"top\"\u003e\n \u003cp\u003ec.542C\u0026gt;A (p.Ala181Glu)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.472406181015453%\" valign=\"top\"\u003e\n \u003cp\u003ePathogenic\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.2317880794702%\" valign=\"top\"\u003e\n \u003cp\u003ePreviously described\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.161147902869757%\" valign=\"top\"\u003e\n \u003cp\u003eTNGS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.077262693156733%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.953642384105961%\" valign=\"top\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.35540838852097%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eTNFRSF13B\u003c/em\u003e (TACI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.368653421633555%\" valign=\"top\"\u003e\n \u003cp\u003eHeterozygous\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.379690949227374%\" valign=\"top\"\u003e\n \u003cp\u003ec.579C\u0026gt;A (p.Cys193Ter)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.472406181015453%\" valign=\"top\"\u003e\n \u003cp\u003ePathogenic\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.2317880794702%\" valign=\"top\"\u003e\n \u003cp\u003ePreviously described\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.161147902869757%\" valign=\"top\"\u003e\n \u003cp\u003eTNGS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.077262693156733%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.953642384105961%\" valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.35540838852097%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eTNFRSF13B\u003c/em\u003e (TACI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.368653421633555%\" valign=\"top\"\u003e\n \u003cp\u003eHeterozygous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.379690949227374%\" valign=\"top\"\u003e\n \u003cp\u003ec.204dupA (p.Leu69ThrfsTer12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.472406181015453%\" valign=\"top\"\u003e\n \u003cp\u003ePathogenic\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.2317880794702%\" valign=\"top\"\u003e\n \u003cp\u003ePreviously described\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.161147902869757%\" valign=\"top\"\u003e\n \u003cp\u003eTNGS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.077262693156733%\" valign=\"top\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.953642384105961%\" valign=\"top\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.35540838852097%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eTNFRSF13B\u003c/em\u003e (TACI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.368653421633555%\" valign=\"top\"\u003e\n \u003cp\u003eHeterozygous\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.379690949227374%\" valign=\"top\"\u003e\n \u003cp\u003ec.204dupA (p.Leu69ThrfsTer12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.472406181015453%\" valign=\"top\"\u003e\n \u003cp\u003ePathogenic\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.2317880794702%\" valign=\"top\"\u003e\n \u003cp\u003ePreviously described\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.161147902869757%\" valign=\"top\"\u003e\n \u003cp\u003eTNGS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.077262693156733%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.953642384105961%\" valign=\"top\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.35540838852097%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eTNFRSF13B\u003c/em\u003e (TACI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.368653421633555%\" valign=\"top\"\u003e\n \u003cp\u003eHeterozygous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.379690949227374%\" valign=\"top\"\u003e\n \u003cp\u003ec.204dupA (p.Leu69ThrfsTer12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.472406181015453%\" valign=\"top\"\u003e\n \u003cp\u003ePathogenic\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.2317880794702%\" valign=\"top\"\u003e\n \u003cp\u003ePreviously described\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.161147902869757%\" valign=\"top\"\u003e\n \u003cp\u003eTNGS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.077262693156733%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.953642384105961%\" valign=\"top\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.35540838852097%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eTNFRSF13B\u003c/em\u003e (TACI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.368653421633555%\" valign=\"top\"\u003e\n \u003cp\u003eHeterozygous\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.379690949227374%\" valign=\"top\"\u003e\n \u003cp\u003ec.418G\u0026gt;A (p.Glu140Lys)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.472406181015453%\" valign=\"top\"\u003e\n \u003cp\u003eVUS (PM2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.2317880794702%\" valign=\"top\"\u003e\n \u003cp\u003ePreviously described\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.161147902869757%\" valign=\"top\"\u003e\n \u003cp\u003eTNGS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.077262693156733%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.953642384105961%\" valign=\"top\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.35540838852097%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eTNFRSF13B\u003c/em\u003e (TACI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.368653421633555%\" valign=\"top\"\u003e\n \u003cp\u003eHeterozygous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.379690949227374%\" valign=\"top\"\u003e\n \u003cp\u003ec.260T\u0026gt;A (p.Ile87Asn)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.472406181015453%\" valign=\"top\"\u003e\n \u003cp\u003ePathogenic\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.2317880794702%\" valign=\"top\"\u003e\n \u003cp\u003ePreviously described\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.161147902869757%\" valign=\"top\"\u003e\n \u003cp\u003eTNGS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.077262693156733%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.953642384105961%\" valign=\"top\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.35540838852097%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eTNFRSF13B\u003c/em\u003e (TACI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.368653421633555%\" valign=\"top\"\u003e\n \u003cp\u003eHeterozygous\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.379690949227374%\" valign=\"top\"\u003e\n \u003cp\u003ec.579C\u0026gt;A (p.Cys193Ter)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.472406181015453%\" valign=\"top\"\u003e\n \u003cp\u003ePathogenic\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.2317880794702%\" valign=\"top\"\u003e\n \u003cp\u003ePreviously described\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.161147902869757%\" valign=\"top\"\u003e\n \u003cp\u003eTNGS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.077262693156733%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.953642384105961%\" valign=\"top\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.35540838852097%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eTNFRSF13B\u003c/em\u003e (TACI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.368653421633555%\" valign=\"top\"\u003e\n \u003cp\u003eHeterozygous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.379690949227374%\" valign=\"top\"\u003e\n \u003cp\u003ec.515G\u0026gt;A (p.Cys172Tyr)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.472406181015453%\" valign=\"top\"\u003e\n \u003cp\u003eVUS (PM2,PP3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.2317880794702%\" valign=\"top\"\u003e\n \u003cp\u003ePreviously described\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.161147902869757%\" valign=\"top\"\u003e\n \u003cp\u003eTNGS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.077262693156733%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.953642384105961%\" valign=\"top\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.35540838852097%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eTNFRSF13B\u0026nbsp;\u003c/em\u003e(TACI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.368653421633555%\" valign=\"top\"\u003e\n \u003cp\u003eHeterozygous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.379690949227374%\" valign=\"top\"\u003e\n \u003cp\u003ec.204dupA (p.Leu69ThrfsTer12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.472406181015453%\" valign=\"top\"\u003e\n \u003cp\u003ePathogenic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.2317880794702%\" valign=\"top\"\u003e\n \u003cp\u003ePreviously described\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.161147902869757%\" valign=\"top\"\u003e\n \u003cp\u003eTNGS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.077262693156733%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.953642384105961%\" valign=\"top\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.35540838852097%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eTNFRSF13B\u0026nbsp;\u003c/em\u003e(TACI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.368653421633555%\" valign=\"top\"\u003e\n \u003cp\u003eHeterozygous\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.379690949227374%\" valign=\"top\"\u003e\n \u003cp\u003ec.310T\u0026gt;C (p.Cys104Arg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.472406181015453%\" valign=\"top\"\u003e\n \u003cp\u003ePathogenic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.2317880794702%\" valign=\"top\"\u003e\n \u003cp\u003ePreviously described\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.161147902869757%\" valign=\"top\"\u003e\n \u003cp\u003eTNGS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.077262693156733%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.953642384105961%\" valign=\"top\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.35540838852097%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eTNFRSF13B\u0026nbsp;\u003c/em\u003e(TACI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.368653421633555%\" valign=\"top\"\u003e\n \u003cp\u003eHeterozygous\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.379690949227374%\" valign=\"top\"\u003e\n \u003cp\u003ec.579C\u0026gt;A (p.Cys193Ter)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.472406181015453%\" valign=\"top\"\u003e\n \u003cp\u003ePathogenic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.2317880794702%\" valign=\"top\"\u003e\n \u003cp\u003ePreviously described\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.161147902869757%\" valign=\"top\"\u003e\n \u003cp\u003eTNGS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.077262693156733%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.953642384105961%\" valign=\"top\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.35540838852097%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eTNFRSF25\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e(Tweak)(April)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.368653421633555%\" valign=\"top\"\u003e\n \u003cp\u003eHeterozygous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.379690949227374%\" valign=\"top\"\u003e\n \u003cp\u003ec.868G\u0026gt;A (p.Glu290Lys)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.472406181015453%\" valign=\"top\"\u003e\n \u003cp\u003eVUS (PM2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.2317880794702%\" valign=\"top\"\u003e\n \u003cp\u003eNovel\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.161147902869757%\" valign=\"top\"\u003e\n \u003cp\u003eWES\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.077262693156733%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.953642384105961%\" valign=\"top\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.35540838852097%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eTNFRSF13C\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e(BAFF-R)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.368653421633555%\" valign=\"top\"\u003e\n \u003cp\u003eHomozygous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.379690949227374%\" valign=\"top\"\u003e\n \u003cp\u003ec.347C\u0026gt;T (p.Ala116Val)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.472406181015453%\" valign=\"top\"\u003e\n \u003cp\u003eVUS(PM2,BP4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.2317880794702%\" valign=\"top\"\u003e\n \u003cp\u003ePreviously described\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.161147902869757%\" valign=\"top\"\u003e\n \u003cp\u003eTNGS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.077262693156733%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.953642384105961%\" valign=\"top\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.35540838852097%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eIL21R\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.368653421633555%\" valign=\"top\"\u003e\n \u003cp\u003eHomozygous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.379690949227374%\" valign=\"top\"\u003e\n \u003cp\u003ec.132delC (p.Ser45fs)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.472406181015453%\" valign=\"top\"\u003e\n \u003cp\u003eLikely Pathogenic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.2317880794702%\" valign=\"top\"\u003e\n \u003cp\u003eNovel\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.161147902869757%\" valign=\"top\"\u003e\n \u003cp\u003eWES\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.077262693156733%\" valign=\"top\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable-2: Our common variable immunodeficiency patients with cytosolic defects (n:10).\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"992\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.27190332326284%\" valign=\"top\"\u003e\n \u003cp\u003ePatient no\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.3444108761329305%\" valign=\"top\"\u003e\n \u003cp\u003eGene\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.983887210473313%\" valign=\"top\"\u003e\n \u003cp\u003eZygosity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.782477341389727%\" valign=\"top\"\u003e\n \u003cp\u003eVariation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.897280966767372%\" valign=\"top\"\u003e\n \u003cp\u003eACMG classification\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.557905337361532%\" valign=\"top\"\u003e\n \u003cp\u003eNovel/\u003c/p\u003e\n \u003cp\u003ePreviously described\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.595166163141993%\" valign=\"top\"\u003e\n \u003cp\u003eMethod\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.566968781470292%\" valign=\"top\"\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.27190332326284%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.3444108761329305%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003ePLCү2\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.983887210473313%\" valign=\"top\"\u003e\n \u003cp\u003eHeterozygous\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.782477341389727%\" valign=\"top\"\u003e\n \u003cp\u003ec.2152A\u0026gt;C (p.Ser718Arg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.897280966767372%\" valign=\"top\"\u003e\n \u003cp\u003eVUS (PM2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.557905337361532%\" valign=\"top\"\u003e\n \u003cp\u003eNovel\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.595166163141993%\" valign=\"top\"\u003e\n \u003cp\u003eTNGS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.566968781470292%\" valign=\"top\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.27190332326284%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.3444108761329305%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003ePLCү2\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.983887210473313%\" valign=\"top\"\u003e\n \u003cp\u003eHeterozygous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.782477341389727%\" valign=\"top\"\u003e\n \u003cp\u003ec.502A\u0026gt;G (p.Thr168Ala)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.897280966767372%\" valign=\"top\"\u003e\n \u003cp\u003eVUS (PM2,BP4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.557905337361532%\" valign=\"top\"\u003e\n \u003cp\u003ePreviously described\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.595166163141993%\" valign=\"top\"\u003e\n \u003cp\u003eTNGS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.566968781470292%\" valign=\"top\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.27190332326284%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.3444108761329305%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003ePLCү2\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.983887210473313%\" valign=\"top\"\u003e\n \u003cp\u003eHeterozygous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.782477341389727%\" valign=\"top\"\u003e\n \u003cp\u003ec.1760G\u0026gt;A (p.Arg587Gln)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.897280966767372%\" valign=\"top\"\u003e\n \u003cp\u003eVUS (PM2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.557905337361532%\" valign=\"top\"\u003e\n \u003cp\u003eNovel\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.595166163141993%\" valign=\"top\"\u003e\n \u003cp\u003eTNGS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.566968781470292%\" valign=\"top\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.27190332326284%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.3444108761329305%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003ePIK3CD\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.983887210473313%\" valign=\"top\"\u003e\n \u003cp\u003eHeterozygous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.782477341389727%\" valign=\"top\"\u003e\n \u003cp\u003ec.401C\u0026gt;T (p.Pro134Leu)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.897280966767372%\" valign=\"top\"\u003e\n \u003cp\u003eVUS (PM2,PP2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.557905337361532%\" valign=\"top\"\u003e\n \u003cp\u003ePreviously described\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.595166163141993%\" valign=\"top\"\u003e\n \u003cp\u003eTNGS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.566968781470292%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.27190332326284%\" valign=\"top\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.3444108761329305%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eLRBA\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.983887210473313%\" valign=\"top\"\u003e\n \u003cp\u003eHomozygous\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.782477341389727%\" valign=\"top\"\u003e\n \u003cp\u003ec.2496C\u0026gt;A (p.Cys832Ter)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.897280966767372%\" valign=\"top\"\u003e\n \u003cp\u003eLikely Pathogenic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.557905337361532%\" valign=\"top\"\u003e\n \u003cp\u003eNovel\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.595166163141993%\" valign=\"top\"\u003e\n \u003cp\u003eTNGS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.566968781470292%\" valign=\"top\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.27190332326284%\" valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.3444108761329305%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eLRBA\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.983887210473313%\" valign=\"top\"\u003e\n \u003cp\u003eHomozygous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.782477341389727%\" valign=\"top\"\u003e\n \u003cp\u003ec.2496C\u0026gt;A (p.Cys832Ter)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.897280966767372%\" valign=\"top\"\u003e\n \u003cp\u003eLikely Pathogenic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.557905337361532%\" valign=\"top\"\u003e\n \u003cp\u003eNovel\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.595166163141993%\" valign=\"top\"\u003e\n \u003cp\u003eTNGS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.566968781470292%\" valign=\"top\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.27190332326284%\" valign=\"top\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.3444108761329305%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eLRBA\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.983887210473313%\" valign=\"top\"\u003e\n \u003cp\u003eHomozygous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.782477341389727%\" valign=\"top\"\u003e\n \u003cp\u003ec.2447del p.(Pro816Leufs4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.897280966767372%\" valign=\"top\"\u003e\n \u003cp\u003eLikely Pathogenic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.557905337361532%\" valign=\"top\"\u003e\n \u003cp\u003eNovel\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.595166163141993%\" valign=\"top\"\u003e\n \u003cp\u003eTNGS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.566968781470292%\" valign=\"top\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.27190332326284%\" valign=\"top\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.3444108761329305%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eTCF3\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.983887210473313%\" valign=\"top\"\u003e\n \u003cp\u003eHeterozygous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.782477341389727%\" valign=\"top\"\u003e\n \u003cp\u003ec.145+7C\u0026gt;A\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.897280966767372%\" valign=\"top\"\u003e\n \u003cp\u003eVUS (PM2,BP4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.557905337361532%\" valign=\"top\"\u003e\n \u003cp\u003eNovel\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.595166163141993%\" valign=\"top\"\u003e\n \u003cp\u003eWES\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.566968781470292%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.27190332326284%\" valign=\"top\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.3444108761329305%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eTCF3\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.983887210473313%\" valign=\"top\"\u003e\n \u003cp\u003eHomozygous\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.782477341389727%\" valign=\"top\"\u003e\n \u003cp\u003ec.1643G\u0026gt;A (p.Arg548His)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.897280966767372%\" valign=\"top\"\u003e\n \u003cp\u003eVUS (PM2,PP3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.557905337361532%\" valign=\"top\"\u003e\n \u003cp\u003eNovel\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.595166163141993%\" valign=\"top\"\u003e\n \u003cp\u003eTNGS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.566968781470292%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.27190332326284%\" valign=\"top\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.3444108761329305%\" valign=\"top\"\u003e\n \u003cp\u003eTCF3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.983887210473313%\" valign=\"top\"\u003e\n \u003cp\u003eHeterozygous,\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.782477341389727%\" valign=\"top\"\u003e\n \u003cp\u003ec.511 A\u0026gt;G\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(p.Lys171Glu)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.897280966767372%\" valign=\"top\"\u003e\n \u003cp\u003eLikely Pathogenic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.557905337361532%\" valign=\"top\"\u003e\n \u003cp\u003eNovel\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.595166163141993%\" valign=\"top\"\u003e\n \u003cp\u003eTNGS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.566968781470292%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable-3:Our common variable immunodeficiency patients with nuclear defects (n:9)\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"952\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.190975865687303%\" valign=\"top\"\u003e\n \u003cp\u003ePatient no\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.499475341028331%\" valign=\"top\"\u003e\n \u003cp\u003eGene\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.196222455403987%\" valign=\"top\"\u003e\n \u003cp\u003eZygosity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.61594963273872%\" valign=\"top\"\u003e\n \u003cp\u003eVariation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.89401888772298%\" valign=\"top\"\u003e\n \u003cp\u003eACMG classification\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.912906610703043%\" valign=\"top\"\u003e\n \u003cp\u003eNovel/\u003c/p\u003e\n \u003cp\u003ePreviously described\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.604407135362015%\" valign=\"top\"\u003e\n \u003cp\u003eMethod\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08604407135362%\" valign=\"top\"\u003e\n \u003cp\u003eRererence\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.190975865687303%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.499475341028331%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eSTAT1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.196222455403987%\" valign=\"top\"\u003e\n \u003cp\u003eHeterozygous\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.61594963273872%\" valign=\"top\"\u003e\n \u003cp\u003ec.295A\u0026gt;G \u0026nbsp;(p.Ile99Val)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.89401888772298%\" valign=\"top\"\u003e\n \u003cp\u003eVUS (PM2,PP2,BP4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.912906610703043%\" valign=\"top\"\u003e\n \u003cp\u003eNovel\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.604407135362015%\" valign=\"top\"\u003e\n \u003cp\u003eTNGS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08604407135362%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.190975865687303%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.499475341028331%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eSTAT1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.196222455403987%\" valign=\"top\"\u003e\n \u003cp\u003eHeterozygous\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.61594963273872%\" valign=\"top\"\u003e\n \u003cp\u003ec.1154 C\u0026gt;T \u0026nbsp;(p.Thr385Met)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.89401888772298%\" valign=\"top\"\u003e\n \u003cp\u003ePathogenic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.912906610703043%\" valign=\"top\"\u003e\n \u003cp\u003ePreviously described\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.604407135362015%\" valign=\"top\"\u003e\n \u003cp\u003eTNGS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08604407135362%\" valign=\"top\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.190975865687303%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.499475341028331%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eSTAT1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.196222455403987%\" valign=\"top\"\u003e\n \u003cp\u003eHeterozygous\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.61594963273872%\" valign=\"top\"\u003e\n \u003cp\u003ec.1154 C\u0026gt;T \u0026nbsp;(p.Thr385Met)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.89401888772298%\" valign=\"top\"\u003e\n \u003cp\u003ePathogenic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.912906610703043%\" valign=\"top\"\u003e\n \u003cp\u003ePreviously described\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.604407135362015%\" valign=\"top\"\u003e\n \u003cp\u003eTNGS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08604407135362%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.190975865687303%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.499475341028331%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eTTC37\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.196222455403987%\" valign=\"top\"\u003e\n \u003cp\u003eHomozygous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.61594963273872%\" valign=\"top\"\u003e\n \u003cp\u003ec.2210T\u0026gt;C \u0026nbsp;(p.Val737Ala)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.89401888772298%\" valign=\"top\"\u003e\n \u003cp\u003eVUS (PM2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.912906610703043%\" valign=\"top\"\u003e\n \u003cp\u003eNovel\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.604407135362015%\" valign=\"top\"\u003e\n \u003cp\u003eTNGS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08604407135362%\" valign=\"top\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.190975865687303%\" valign=\"top\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.499475341028331%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003ePTEN\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.196222455403987%\" valign=\"top\"\u003e\n \u003cp\u003eHeterozygous\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.61594963273872%\" valign=\"top\"\u003e\n \u003cp\u003ec.389 G\u0026gt;C \u0026nbsp;(p.Arg130Pro)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.89401888772298%\" valign=\"top\"\u003e\n \u003cp\u003ePathogenic\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.912906610703043%\" valign=\"top\"\u003e\n \u003cp\u003ePreviously described\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.604407135362015%\" valign=\"top\"\u003e\n \u003cp\u003eWES\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08604407135362%\" valign=\"top\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.190975865687303%\" valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.499475341028331%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eTRNT1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.196222455403987%\" valign=\"top\"\u003e\n \u003cp\u003eHomozygous,\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.61594963273872%\" valign=\"top\"\u003e\n \u003cp\u003ec.914A\u0026gt;T \u0026nbsp;(p.Asp305Val)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.89401888772298%\" valign=\"top\"\u003e\n \u003cp\u003eVUS (PM2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.912906610703043%\" valign=\"top\"\u003e\n \u003cp\u003eNovel\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.604407135362015%\" valign=\"top\"\u003e\n \u003cp\u003eTNGS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08604407135362%\" valign=\"top\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.190975865687303%\" valign=\"top\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.499475341028331%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eIKZF1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.196222455403987%\" valign=\"top\"\u003e\n \u003cp\u003eHeterozygous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.61594963273872%\" valign=\"top\"\u003e\n \u003cp\u003ec.488A\u0026gt;C \u0026nbsp;(p.His163Pro)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.89401888772298%\" valign=\"top\"\u003e\n \u003cp\u003eLikely Pathogenic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.912906610703043%\" valign=\"top\"\u003e\n \u003cp\u003eNovel\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.604407135362015%\" valign=\"top\"\u003e\n \u003cp\u003eTNGS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08604407135362%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.190975865687303%\" valign=\"top\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.499475341028331%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eNFKB2\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.196222455403987%\" valign=\"top\"\u003e\n \u003cp\u003eHeterozygous\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.61594963273872%\" valign=\"top\"\u003e\n \u003cp\u003ec.2557C\u0026gt;T (p.Arg853Ter)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.89401888772298%\" valign=\"top\"\u003e\n \u003cp\u003ePathogenic\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.912906610703043%\" valign=\"top\"\u003e\n \u003cp\u003ePreviously described\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.604407135362015%\" valign=\"top\"\u003e\n \u003cp\u003eTNGS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08604407135362%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.190975865687303%\" valign=\"top\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.499475341028331%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eNFKB2\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.196222455403987%\" valign=\"top\"\u003e\n \u003cp\u003eHeterozygous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.61594963273872%\" valign=\"top\"\u003e\n \u003cp\u003ec.2557C\u0026gt;T (p.Arg853Ter)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.89401888772298%\" valign=\"top\"\u003e\n \u003cp\u003ePathogenic\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.912906610703043%\" valign=\"top\"\u003e\n \u003cp\u003ePreviously described\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.604407135362015%\" valign=\"top\"\u003e\n \u003cp\u003eWES\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.08604407135362%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable-4: Our common variable immunodeficiency patients with other defects (n: 3)\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"943\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.786850477200424%\" valign=\"top\"\u003e\n \u003cp\u003ePatient no\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.028632025450689%\" valign=\"top\"\u003e\n \u003cp\u003eGene\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.028632025450689%\" valign=\"top\"\u003e\n \u003cp\u003eZygosity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.08695652173913%\" valign=\"top\"\u003e\n \u003cp\u003eVariation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.983032873807%\" valign=\"top\"\u003e\n \u003cp\u003eACMG classification\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.05832449628844%\" valign=\"top\"\u003e\n \u003cp\u003eNovel/\u003c/p\u003e\n \u003cp\u003ePreviously described\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.013785790031813%\" valign=\"top\"\u003e\n \u003cp\u003eMethod\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.013785790031813%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.786850477200424%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.028632025450689%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003ePRKDC\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.028632025450689%\" valign=\"top\"\u003e\n \u003cp\u003eHomozygous\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.08695652173913%\" valign=\"top\"\u003e\n \u003cp\u003ec.10143C\u0026gt;G (p.Phe3381Leu)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.983032873807%\" valign=\"top\"\u003e\n \u003cp\u003eVUS (PM2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.05832449628844%\" valign=\"top\"\u003e\n \u003cp\u003ePreviously described\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.013785790031813%\" valign=\"top\"\u003e\n \u003cp\u003eTNGS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.013785790031813%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.786850477200424%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.028632025450689%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eMALT1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.028632025450689%\" valign=\"top\"\u003e\n \u003cp\u003eHomozygous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.08695652173913%\" valign=\"top\"\u003e\n \u003cp\u003ec.2418G\u0026gt;C (p.Glu806Asp)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.983032873807%\" valign=\"top\"\u003e\n \u003cp\u003eVUS (PM2,BP4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.05832449628844%\" valign=\"top\"\u003e\n \u003cp\u003eNovel\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.013785790031813%\" valign=\"top\"\u003e\n \u003cp\u003eTNGS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.013785790031813%\" valign=\"top\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.786850477200424%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.028632025450689%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eMAGT1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.028632025450689%\" valign=\"top\"\u003e\n \u003cp\u003eHemizygous\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.08695652173913%\" valign=\"top\"\u003e\n \u003cp\u003ec.340C\u0026gt;T (p.Gln114Ter)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.983032873807%\" valign=\"top\"\u003e\n \u003cp\u003eLikely Pathogenic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.05832449628844%\" valign=\"top\"\u003e\n \u003cp\u003eNovel\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.013785790031813%\" valign=\"top\"\u003e\n \u003cp\u003eTNGS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.013785790031813%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"common variable immune deficiency, targeted next generation sequencing, whole exome sequencing ","lastPublishedDoi":"10.21203/rs.3.rs-3093761/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3093761/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eIdentification of the causes of monogenetic common variable immune deficiency (CVID) patients has rapidly increased in the last years by means of worldwide availability of appropriate genetic diagnostic methods. However, up to date, very limited numbers of reports demostrating the role of geography, ethnicity and consanguinity have been published. Here, we reported the first study of Turkish CVID patients and compared them with the results of three countries from America, Europe and Asia. A total of 100 children diagnosed as CVID according to the criteria of European Society for Immunodeficiencies were enrolled and they were genetically analyzed by using Targeted Next Generation Sequencing and Whole Exome Sequencing. The median age of our patients was 5.8 years (range, 3.0-16.0 years) at clinical diagnosis and 9.0 years (range, 4.8-21.0 years) at the time of genetic diagnosis. The consanguianity rate was 24%. Disease-causing pathogenic mutations were defined in 40% of patients in a total of 17 different genes. Sixteen of 40 identified mutations were novel (40%). We determined 18 surface molecular defects, 10 cytosolic defects, 9 nuclear defects and 3 others. In our cohort, the most common gene was \u003cem\u003eTACI \u003c/em\u003e\u0026nbsp;(15/40 in mutation identified cases and 15/100 in all cases) followed by the others such as \u003cem\u003ePLCү2, LRBA, TCF3 \u003c/em\u003eand\u003cem\u003e STAT1. \u003c/em\u003eIn contrast to our expectations, our results were more similar to American and European population rather than Asians, although we also have high consanguinity rates and live on the geography between Europe and Asia. Genetic investigation is a great challenge, because of the complexity and heterogenity of the disease and each country has to know their own current genetic landscape in CVID for a better and successful management of the patients.\u003c/p\u003e","manuscriptTitle":"Current Genetic Defects in Common Variable Immune Deficiency Patients on the Geography Between Europe and Asia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-06-28 05:27:23","doi":"10.21203/rs.3.rs-3093761/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a051867b-eec9-4a36-bc86-3e42a92f7d4c","owner":[],"postedDate":"June 28th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-08-02T19:28:39+00:00","versionOfRecord":[],"versionCreatedAt":"2023-06-28 05:27:23","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3093761","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3093761","identity":"rs-3093761","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}