Curation Of Genes Associated with Primary Antibody Deficiencies Using A ClinGen Framework

The Antibody Deficiencies Gene Curation Expert Panel (AD-GCEP, Table 1**) was convened in 2020 as part of the Clinical Genome Resource (ClinGen), an NIH funded program to build a genomic knowledge base publicly available for laboratories, clinicians, and scientists. The objective of the AD-GCEP was to curate genes associated with inborn errors of immunity (IEIs) that cause antibody deficiencies with or without quantitative B-cell defects and other phenotypic manifestations. Using a gene-disease validity scoring system established by ClinGen, the gene curation provides guidelines for definitive, strong, moderate, limited, or disputed classification depending on the reported evidence. We selected 55 genes from Table 3 of the International Union of Immunological Societies (IUIS 2022) classification of IEIs. As of November 2022, 46 of these have been curated (Table 2). Several of these genes are associated with multiple disease entities, for which the ClinGen lumping-splitting criteria were applied. Through curation, the GCEP has identified 53 gene-disease relationships. Twenty-six (49%) were definitive classifications with abundant genetic and experimental evidence. Only three genes reached a strong classification (5.7%): RAC2 deficiency, FNIP1-associated syndrome, and SPI1 deficiency. In contrast, insufficient evidence led to moderate classifications for eight (15.1%) and limited classifications for thirteen (24.5%) gene-disease relationships. Of note, two gene-disease relationships (3.7%) were disputed: BTK-isolated growth hormone deficiency (GHD) type III, and common variable immunodeficiency associated with INO80 variants (CVID1). The single family cohort reported with the BTK variant and GHD was later shown to have another molecular etiology, while the INO80 variants had a population frequency too high to be regarded as disease-causing. An additional ten genes need to be curated to complete the current list of antibody defects. Additionally, the AD-GCEP has collaborated with other GCEPs to curate related genes such as MOGS, ATP6AP1, CD40L, KMT2A, MSH6, GATA2, PMS2, BLK and BRWD1, which cause antibody deficiency as one component of a more extensive phenotype series. Information about these genes is provided in Table 3. In summary, the work of this GCEP represents the first comprehensive gene curation for antibody deficiencies.Table 1Members of the Antibody Deficiency (AD) GCEPMemberRoleRoshini S. Abraham, PhD, D (ABMLI)Co-Chair, ExpertStuart Tangye, PhD.Co-Chair, ExpertForum Raval, Ph.D.Co-Chair ExpertAlejandro Nieto, Ph.DCoordinatorKathleen E. Sullivan, MD, PhDExpertAnna Sediva, MDExpertKejian Zhang, MDExpertStephen Jolles, MDExpertPJ Maglione, MD, PhDExpertCapucine Picard, MD, PhDExpertCraig Platt, MD, PhDExpertAnita Chandra, PhDExpertKlaus Warnatz, MDExpertAdrian Harry Lesmana, MDExpertShruthi Mohan, PhDBiocuratorJustyne Ross, PhDBiocuratorMichelle Paczosa, PhDBiocuratorRasha Soliman, MD, MSBiocuratorOlga Sarmento, PhDBiocuratorErmal Aliu, MDBiocuratorTable 2Classification of genes curated by the Antibody Deficiencies GCEP (AD-GCEP)GeneDiseaseMOIClassificationAICDAHyper-IgM syndrome type 2 (AID deficiency)ARDefinitiveATMAtaxia telangiectasia (AT)ARDefinitiveBLNKAgammaglobulinemia 4, autosomal recessive (BLNK-associated agammaglobulinemia)ARDefinitiveBTKBruton-type agammaglobulinemia (X-linked agammaglobulinemia)XLRDefinitiveBTKIsolated growth hormone deficiency type IIIXLRDisputedCARD11BENTA (B cell expansion with NFκB and T cell anergy) diseaseADDefinitiveCARD11Severe combined immunodeficiency due to CARD11 deficiencyARDefinitiveCARD11Immunodeficiency 11b with atopic dermatitis (CARD11 + atopic dermatitis)ADDefinitiveCD19Immunodeficiency, common variable, 3 (CD19 deficiency)ARDefinitiveCD79AAgammaglobulinemia 3, autosomal recessive (Ig-alpha deficiency)ARDefinitiveCD79BAgammaglobulinemia 6, autosomal recessive (Ig-beta deficiency)ARDefinitiveCR2Immunodeficiency, common variable, 7 (CD21 deficiency)ARDefinitiveCTLA4Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsuffiency (CHAI)ADDefinitiveIGHMAutosomal recessive agammaglobulinemia 1 (Mu-heavy chain deficiency)ARDefinitiveIKZF1Pancytopenia due to IKZF1mutations; IKAROS deficiencyADDefinitiveIKZF1Autoimmune disease, IKAROS defectADModerateLRBACombined immunodeficiency due to LRBA deficiency; LATAIEARDefinitiveNFKB1Immunodeficiency, common variable, 12 (NFkB1 deficiency)ADDefinitiveNFKB2Immunodeficiency, common variable, 10 (NFkB2 deficiency, DAVID syndrome)ADDefinitivePIK3CDImmunodeficiency 14b, autosomal recessiveARDefinitivePIK3CDImmunodeficiency 14 (APDS type 1; activated p110-delta syndrome, PASLI disease)ADDefinitivePIK3R1Immunodeficiency 36 (APDS type 2; gain-of-function disease in PI3K regulatory subunits)ADDefinitivePIK3R1Agammaglobulinemia 7, autosomal recessive (p85alpha subunit defect)ARLimitedTNFRSF13BImmunodeficiency, common variable, 2 (TACI deficiency)ARDefinitiveCD40Hyper-IgM syndrome type 3 (MONDO:0011735), CD40 deficiencyARDefinitiveTCF3Autosomal agammaglobulinemia (MONDO:0011096)/(agammaglobulinemia 8B)/AD (agammaglobulinemia 8A)ARDefinitiveTRNT1SIFD (sideroblastic anemia, B cell immunodeficiency, periodic fevers and developmental delay) retinitis pigmentosa with erythrocytic microcytosisARDefinitiveICOSCommon variable immunodeficiency, ICOS deficiencyARDefinitiveIL21RImmunodeficiency 56, IL-21R deficiencyARDefinitiveFNIP1FNIP1-associated syndrome, FNIP1 deficiencyARStrongSPI1Agammaglobulinemia 10, PU.1 deficiencyADStrongIGLL1Agammaglobulinemia 2, autosomal recessive, Ig light chain deficiency (lambda-like)ARModerateRAC2Immunodeficiency 73b with defective neutrophil chemotaxis and lymphopenia, Rac2 deficiency (loss-of-function, LOF) and Rac2 gain-of-function (GOF)ADStrongRAC2Immunodeficiency 73c with defective neutrophil chemotaxis and hypogammaglobulinemia, Rac2 deficiency (loss-of-function, LOF) and Rac2 gain-of-function (GOF)ARModerateRAC2Neutrophil immunodeficiency syndrome, Rac2 deficiency (loss-of-function, LOF) and Rac2 gain-of-function (GOF)ADModerateSEC61A1SEC61A1 deficiency, plasma cell deficiencyADModerateSLC39A7Agammaglobulinemia 9, ZIP7 deficiencyARModerateTOP2BB-cell immunodeficiency, distal limb anomalies, and urogenital malformations, Hoffman syndromeADModerateUNGHyper-IgM syndrome type 5, UNG deficiencyARModerateARHGEF1Immunodeficiency 62, ARHGEF1 deficiencyARLimitedCD81Immunodeficiency, common variable, 6, CD81 deficiencyARLimitedCTNNBL1Common variable immunodeficiency, immunodeficiency 99 with hypogammaglobulinemia and autoimmune cytopeniasARLimitedIGKCRecurrent infections associated with rare immunoglobulin isotypes deficiency, Ig kappa light chain deficiencyARLimitedIRF2BP2Immunodeficiency, common variable, 14, IRF2BP2 deficiencyADLimitedMS4A1Immunodeficiency, common variable, 5, CD20 deficiencyARLimitedPOU2AF1Agammaglobulinemia, Bob1 deficiencyARLimitedSH3KBP1Immunodeficiency 61, CIN85 deficiencyXLRLimitedTNFRSF13CImmunodeficiency, common variable, 4, BAFF-R deficiencyARLimitedTNFSF12Common variable immunodeficiency, TWEAK deficiencyADLimitedTNFSF13Common variable immunodeficiency, APRIL deficiencyARLimitedIL21Common variable immunodeficiency 11, IL-21 deficiencyARLimitedINO80immunodeficiency, common variable, 1, INO80 deficiencyARDisputedAR: autosomal recessive; AD: autosomal dominant; XLR: X-linked recessiveTable 3Genes associated with antibody deficiencies curated in collaboration with other GCEPsGeneDiseaseInheritanceCollaborating GCEPClassificationMOGSMOGS-congenital disorder of glycosylationARGeneral Inborn Errors of Metabolism GCEPDefinitiveATP6AP1Congenital disorder of glycosylation type IIXLRGeneral Inborn Errors of Metabolism GCEPLimitedCD40LX-linked Hyper IgM syndromeXLRSCID-CIDDefinitiveKMT2AWiedemann-Steiner syndromeADSyndromic Disorders GCEPDefinitiveMSH6mismatch repair cancer syndrome 1ARHereditary Cancer GCEPDefinitiveGATA2Mono-MAC syndrome, Familial myeloid leukemia, DCML deficiency, GATA2 haploinsufficiencyADHereditary CancerDefinitivePMS2Mismatch repair cancer syndrome 1ARHereditary CancerDefinitiveBLKMonogenic diabetesADMonogenic DiabetesRefutedBRWD1Primary Ciliary Dyskinesia (PCD)ARMotile CiliopathyRefutedBRWD1Agammaglobulinemia, B cell deficiencyADTransferred to AD-GCEPLimited