J Clin Immunol DOI 10.1007/s10875-015-0201-1

ORIGINAL RESEARCH

Primary Diseases: an Update on the Classification from the International Union of Immunological Societies Expert Committee for 2015

1,2 3,4 5 1,6,7,8,9 Capucine Picard & Waleed Al-Herz & Aziz Bousfiha & Jean-Laurent Casanova & 10 6 11 Talal Chatila & Mary Ellen Conley & Charlotte Cunningham-Rundles & 12 13 14 15 Amos Etzioni & Steven M. Holland & Christoph Klein & Shigeaki Nonoyama & 16 17,18 19 20 Hans D. Ochs & Eric Oksenhendler & Jennifer M. Puck & Kathleen E. Sullivan & 21,22,23 24 25 Mimi L K. Tang & Jose Luis Franco & H. Bobby Gaspar

Received: 20 July 2015 /Accepted: 20 September 2015 # The Author(s) 2015. This article is published with open access at Springerlink.com

Abstract We report the updated classification of primary im- previous version, 34 new gene defects are reported in this up- munodeficiencies compiled by the Primary Immunodeficiency dated version. For each disorder, the key clinical and laboratory Expert Committee (PID EC) of the International Union of features are provided. In this new version we continue to see Immunological Societies (IUIS). In the two years since the the increasing overlap between immunodeficiency, as

* H. Bobby Gaspar 12 Meyer Children’s Hospital-Technion, Haifa, Israel [email protected] 13 Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA 1 Laboratory of Human Genetics of Infectious Diseases, Necker 14 Dr von Hauner Children’s Hospital, Ludwig-Maximilians-University Branch, INSERM UMR1163, Necker Hospital for Sick Children, Munich, Munich, Germany Paris, France 15 Department of Pediatrics, National Defense Medical College, 2 Centre d’étude des déficits immunitaires (CEDI), Hôpital Saitama, Japan Necker-Enfants Malades, AP-HP, Paris, France 16 Department of Pediatrics, University of Washington and Seattle 3 Department of Pediatrics, Faculty of Medicine, Kuwait University, Children’s Research Institute, Seattle, WA, USA Kuwait City, Kuwait 17 Department of Clinical Immunology, Hôpital Saint-Louis, 4 Allergy and Clinical Immunology Unit, Department of Pediatrics, Assistance Publique-Hôpitaux de Paris, Paris, France Al-Sabah Hospital, Kuwait City, Kuwait 18 Université Paris Diderot, Sorbonne Paris Cité, Paris, France 5 Clinical Immunology Unit, Casablanca Children’s Hospital, Ibn Rochd Medical School, King Hassan II University, 19 Department of Pediatrics, University of California San Francisco and Casablanca, Morocco UCSF Benioff Children’s Hospital, San Francisco, CA, USA 6 St. Giles Laboratory of Human Genetics of Infectious Diseases, 20 Division of Allergy Immunology, Department of Pediatrics, The Rockefeller Branch, The Rockefeller University, New York, NY, Children’s Hospital of Philadelphia, Philadelphia, PA, USA USA 21 Murdoch Childrens Research Institute, Melbourne, VIC, Australia 7 Howard Hughes Medical Institute, New York, NY, USA 22 Department of Paediatrics, University of Melbourne, 8 University Paris Descartes, Imagine Institute, Paris, France Melbourne, VIC, Australia 9 Pediatric Hematology & Immunology Unit, Necker Hospital for Sick 23 Department of Allergy and Immunology, Royal Children’s Hospital, Children, Paris, France Melbourne, Australia 10 Division of Immunology, Children’s Hospital Boston, Boston, MA, 24 Group of Primary , University of Antioquia, USA Medellin, Colombia 11 Department of Medicine and Pediatrics, Mount Sinai School of 25 UCL Institute of Child Health, 30, Guilford Street, London WC1N Medicine, New York, NY, USA 1EH, UK JClinImmunol manifested by and/or malignancy, and immune dys- The title of Table 6 has now been slightly changed to regulation, as manifested by auto-inflammation, auto-immuni- ‘Defects in intrinsic and innate immunity’ and contains de- ty, and/or allergy. There is also an increased number of genetic fects characterized by susceptibility to specific organisms. defects that lead to susceptibility to specific organisms which For this reason, the MSMDs (Mendelian Susceptibility to reflects the finely tuned nature of immune defense systems. Mycobacterial Disease) are now in Table 6,havingpreviously This classification is the most up to date catalogue of all known been in Table 5 (Phagocytic Disorders). and published primary immunodeficiencies and acts as a cur- In previous editions, we have placed an asterisk against rent reference of the knowledge of these conditions and is an conditions in which 10 or fewer individuals had been de- important aid for the genetic and molecular diagnosis of pa- scribed in the literature. However, this is now felt to be an tients with these rare diseases. artificial indicator as, once described, a condition may be found in additional patients but not necessarily reported. For this reason, there is no specific indicator of the number of Keywords Primary immunodeficiencies . classification . patients identified or reported. genetic defects There is a growing appreciation of wide phenotypic vari- ability for many of the individual specific gene defects, reflecting not only the variety of mutations within each gene Background but also host and/or environmental modifying factors that may impact the phenotype even between individuals with the same The International Union of Immunological Societies (IUIS) mutation within the same gene. The complexities of these Expert Committee on Primary Immunodeficiency met in conditions in terms of clinical and immunological presenta- London on the 14th and 15th March 2015 to update the clas- tion and heterogeneity cannot easily be captured in the limited sification of human primary immunodeficiencies (PIDs). This space of a table format. For this reason, the furthest right report represents the most current and complete catalogue of column contains the Online Mendelian Inheritance in Man known PIDs. It serves as a reference for these conditions and (OMIM) reference for each condition to allow access to a provides a framework to help in the diagnostic approach to source of greater detail and updated information as to the patients suspected to have PID. phenotype. As in previous reports, we have classified the condi- A number of the new genes included in this edition of the tions into major groups of PIDs and these are now repre- classification tables are molecules associated not only with the sented in 9 different tables (Tables 1, 2, 3, 4, 5, 6, 7,8 and immune system, but also with more generic cellular functions; 9). In each table, we list the condition, its genetic defect if such defects result in both immunological and non- known and the major immunological and in some condi- immunological abnormalities. In addition, there are a number tions the non-immunological abnormalities associated of gain-of-function (GOF) mutations identified such as in with the disease. This year we have added the gene PIK3CD. In CARD11 and STAT1 for example, there are both OMIM number as well as the phenotype OMIM number autosomal dominant GOF and autosomal recessive loss of for ease of reference. function variants and these different modes of inheritance in The classification this year differs in a number of ways the same gene lead to different functional consequences and from the previous edition published in 2014. Importantly, hence different immunological and clinical phenotypes. The each defect is now listed in only one table. The diverse other trend that is increasingly observed is the increase in immunological phenotypes of many conditions imply that disorder of immunedysregulation rather than pure a very large number of conditions could very readily be immunodeficiency. listed in multiple tables. However, with the increasing The goal of the IUIS Expert Committee on Primary number of identified defects, this would make each table Immunodeficiencies is to increase awareness, facilitate rec- large and cumbersome. For this reason, we chose to list ognition and promote optimal treatment for patients with each defect in one table only and to place it according to Primary Immunodeficiencies. In addition to the current the most pronounced and fundamental defect. For this report and previous ‘classification table’ publications, the reason and as an example, CD40L deficiency is now committee has also produced a ‘Phenotypic Approach for found in Table 1 amongst combined immunodeficiencies, IUIS PID classification and Diagnosis: Guidelines for because CD40L is a T cell signaling molecule whose ab- Clinicians at the Bedside,’ which aims to lead physicians sence leads to both cellular and humoral defects, even to particular groups of PIDs starting from clinical features though it was originally described as an antibody deficien- and combining routine immunological investigations. This cy. Although some of our placements may be disputed, will be further updated to include the newly identified the committee came to these decisions after much thought defects. Together these contributions will hopefully allow and deliberation. a practical clinical framework for PID diagnosis. lnImmunol Clin J Table 1 Immunodeficiencies affecting cellular and humoral immunity

Disease Genetic defect/Presumed Inheritance Circulating T cells Circulating B cells Serum Ig Associated Features Phenotype pathogenesis OMIM Gene OMIM number

T−B+ Severe Combined Immunodeficiency (SCID) γcdeficiency MutationofIL2RG XL Markedly decreased Normal or increased Decreased Markedly decreased 300400 Defect in γ chain of NK cells; receptors for IL-2, -4, -7, -9, -15, -21 308380 JAK3 deficiency Mutation of JAK3 AR Markedly decreased Normal or increased Decreased Markedly decreased 600802 Defect in Janus NK cells; activating kinase 3 600173 IL7Rα deficiency Mutation of IL7RA AR Markedly decreased Normal or increased Decreased Normal NK cells 608971 Defect in IL-7 receptor α chain 146661 CD45 deficiency Mutation of PTPRC AR Markedly decreased Normal Decreased Normal γ/δ Tcells 608971 Defect in CD45 151460 CD3δ deficiency Mutation of CD3D AR Markedly decreased Normal Decreased Normal NK cells 615617 Defect in CD3δ,chain No γ/δ Tcells of T cell antigen receptor complex 186790, CD3ε deficiency Mutation of CD3E AR Markedly decreased Normal Decreased Normal NK cells 615615 Defect in CD3ε chain No γ/δ Tcells of T cell antigen receptor complex 186830, CD3ζ deficiency Mutation of CD3Z AR Markedly decreased Normal Decreased Normal NK cells 610163 Defect in CD3ζ No γ/δ Tcells chain of T cell antigen receptor complex 186780 Coronin-1A deficiency Mutation of CORO1A AR Markedly decreased Normal Decreased Detectable thymus 615401 Defective thymic EBV-associated B-cell egress of T cells lymphoproliferation and defective Tcelllocomotion 605000 T−B− SCID DNA recombination defects (for additional DNA repair defects see Table 2) RAG 1 deficiency Mutation of RAG1 AR Markedly decreased Markedly decreased Decreased 601457 Defective VDJ recombination; defect of recombinase activating gene (RAG) 1 179615 RAG 2 deficiency Mutation of RAG2 AR Markedly decreased Markedly decreased Decreased 601457 Defective VDJ recombination; Table 1 (continued)

Disease Genetic defect/Presumed Inheritance Circulating T cells Circulating B cells Serum Ig Associated Features Phenotype pathogenesis OMIM Gene OMIM number

defect of recombinase activating gene (RAG) 2 179616 DCLRE1C (Artemis) Mutation of ARTEMIS AR Markedly decreased Markedly decreased Decreased Radiation sensitivity 602450 deficiency Defective VDJ recombination; defect in Artemis DNA recombinase-repair protein 605988 DNA PKcs deficiency Mutation of PRKDC AR Markedly decreased Markedly decreased variable Radiation sensitivity, 615966 Defective VDJ microcephaly and recombination; developmental defects defect in DNA Autoimmunity PKcs and granuloma Recombinase repair protein 600899 Cernunnos/XLF Mutation of Cernunnos AR Markedly decreased Markedly decreased Decreased Radiation sensitivity, 611291 deficiency Defective VDJ microcephaly and recombination; developmental defects defect in Cernunnos 611290 DNA ligase IV deficiency Mutation of LIG4 AR Markedly decreased Markedly decreased Decreased Radiation sensitivity, 606593 Defective VDJ recombination; microcephaly and defect in DNA developmental defects ligase IV 601837 Reticular dysgenesis, Mutation of AK2 AR Markedly decreased Decreased or normal Decreased Granulocytopenia and deafness 267500 AK2 deficiency Defective maturation of lymphoid and myeloid cells (stem cell defect) Defect in mitochondrial adenylate kinase 2. 103020 Adenosine deaminase Mutation of ADA AR Absent from birth (null mutations) Absent from birth of Progressive decrease Decreased NK cells, often with 102700 (ADA) deficiency Absent ADA activity, elevated or progressive decrease progressive decrease costochondral junction lymphotoxic metabolites flaring, neurological (dATP, S-adenosyl homocysteine) features, hearing impairment, 608958 lung and liver manifestations; partial ADA deficiency may lead to delayed or milder presentation Combined immunodeficiencies generally less profound than severe combined immunodeficiency DOCK2 deficiency Mutations in DOCK2 required AR Decreased. Poor response Normal Decreased/ Normal. Normal NK numbers, but defective 616433 for RAC1 activation, to PHA. Low TRECs Poor antibody function. Impaired interferon

actin polymerization, responses responses in hematopoietic and JClinImmunol T-cell proliferation, non-hematopoietic cells chemokine-induced lymphocyte migration and NK-cell degranulation 603122 lnImmunol Clin J Table 1 (continued)

Disease Genetic defect/Presumed Inheritance Circulating T cells Circulating B cells Serum Ig Associated Features Phenotype pathogenesis OMIM Gene OMIM number

CD40 ligand deficiency Mutation of CD40LG Defects in XL Normal; may sIgM+ and sIgD+ Bcells IgM increased or , thrombocytopenia; 308230 CD40 ligand (CD40L; progressively decrease present, normal, other hemolytic anemia, biliary also called TNFSF5 other surface isotype isotypes decreased tract and liver disease, or CD154) cause defective positive B cells absent opportunistic isotype switching and impaired dendritic cell signaling 300386 CD40 deficiency Mutation of CD40 (also called AR Normal IgM+ and IgD+ Bcellspresent, IgM increased or Neutropenia, gastrointestinal 606843 TNFRSF5) other isotypes absent normal, other and liver/biliary tract Defects in CD40 cause defective isotypes decreased disease, opportunistic infections isotype switching and impaired dendritic cell signaling 109535 ICOS deficiency Mutations in ICOS; a co-stimulatory AR Normal Normal Low Recurrent infections; autoimmunity, 607594 molecule expressed on T cells gastroenteritis, may have 604558 granulomas CD3γ deficiency Mutation of CD3G. Defect in CD3γ AR Normal, but reduced TCR Normal Normal 615607 component of the T cell expression antigen receptor complex 186740 CD8 deficiency Mutation of CD8A. Defects of CD8 AR Absent CD8, normal Normal Normal α chain, important for maturation CD4 cells and function of CD8 T cells 186910 ZAP-70 deficiency Mutation in ZAP70 intracellular AR Decreased CD8, normal Normal Normal Autoimmunity in some cases 269840 signaling kinase, acts CD4 cells downstream of TCR 176947 MHC class I deficiency Mutations in TAP1,gene, AR Decreased CD8, normal Normal Normal Vasculitis; pyoderma gangrenosum 604571 causing MHC class CD4 cells; Inon-expression absent MHC I expression on 170260 lymphocytes MHC class I deficiency Mutations in TAP2,gene, AR Decreased CD8, normal Normal Normal Vasculitis; pyoderma gangrenosum 604571 causing MHC class CD4 cells; Inon-expression absent MHC I expression on 170261 lymphocytes MHC class I deficiency Mutations in TAPBP (tapasin) AR Decreased CD8, normal Normal Normal Vasculitis; pyoderma gangrenosum 604571 gene, causing MHC CD4 cells; class I non-expression absent MHC I expression on 601962 lymphocytes MHC class I deficiency Mutations in B2M gene, AR Decreased CD8, normal Normal Normal Sinopulmonary infections, cutaneous not yet causing MHC class CD4 cells; granuloma, hypoproteinemia. assigned Inon-expression absent MHC I expression on Absent expression of β2m 109700 lymphocytes associated proteins like MHC-I, CD1a, and CD1b, CD1c on β2m- deficient cells MHC class II deficiency Mutation in transcription AR Decreased CD4 cells Normal Normal or decreased Failure to thrive, diarrhea, respiratory 209920 group A factors for MHC class II Absent MHC II expression on tract infections liver/biliary proteins (CIITA gene) lymphocytes tract disease 600005 Table 1 (continued)

Disease Genetic defect/Presumed Inheritance Circulating T cells Circulating B cells Serum Ig Associated Features Phenotype pathogenesis OMIM Gene OMIM number

MHC class II deficiency Mutation in transcription AR Decreased CD4 cells Normal Normal or decreased Failure to thrive, diarrhea, 209920 group B factors for MHC class II Absent MHC II expression on respiratory tract infections proteins RFXANK gene lymphocytes liver/biliary tract disease 603200 MHC class II deficiency Mutation in transcription AR Decreased CD4 cells Normal Normal or decreased Failure to thrive, diarrhea, respiratory 209920 group C factors for MHC class II Absent MHC II expression on tract infections liver/biliary tract proteins RFX5,gene) lymphocytes disease 601863 MHC class II deficiency Mutation in transcription factors AR Decreased CD4 cells Normal Normal or decreased Failure to thrive, diarrhea, respiratory 209920 group D for MHC class II proteins Absent MHC II expression on tract infections liver/biliary (RFXAP gene lymphocytes tract disease 601861 ITK deficiency Mutations in ITK encoding IL-2 AR Progressive decrease Normal Normal or decreased EBV associated B cell lymphop- 613011 inducible T cell kinase required roliferation, lymphoma for TCR-mediated activation Normal or decreased IgG 186973 MAGT1 deficiency Mutations in MAGT1,Impaired XL Decreased CD4 cells reduced numbers Normal Normal EBV infection, lymphoma; 300853 Mg++ flux leading to impaired of RTE, impaired T-cell viral infections, respiratory TCR signaling 300715 proliferation in response to CD3 and GI infections, DOCK8 deficiency Mutations in DOCK8 encoding AR Decreased; Impaired T lymphocyte Decreased; low Low IgM, increased IgE Decreased NK cells with impaired f 243700 adedicatorofcytokinesis proliferation; Treg deficiency CD27+ memory unction, hypereosinophilia, regulator of intracellular and poor function Bcells recurrent infections; severe actin reorganisation atopy, extensive cutaneous 611432 viral and staphylococcal infections, susceptibility to cancer. Defects in peripheral B tolerance. RhoH deficiency Mutations in RHOH – an atypical AR Normal Normal Normal HPV infection, lymphoma, not yet Rho GTPase transducing low naïve T cells and RTE, restricted lung granulomas, molluscum assigned signals downstream of Tcellrepertoireandimpaired contagiosum, various membrane receptors Tcellsproliferationinresponse 602037 to CD3 stimulation. MST1 deficiency Mutations in STK4 – aserine/ AR Decreased increased proportion Decreased High Recurrent bacterial, viral, and 614868 threonine kinase of terminal differentiated effector candidal 604965 memory cells (TEMRA), low infections; intermittent naïve T cells, restricted neutropenia; Tcellrepertoireinthe EBV-driven lymphoproliferation; TEMRA population and lymphoma; Congenital heart impaired T cells proliferation disease, autoimmune cytopenias; HPV infection. TCRα deficiency Mutations in TRAC – essential AR Normal All CD3 T cells expressed Normal Normal Recurrent viral, bacterial and 615387 component of the T cell receptor TCRγδ (or may be better fungal infections, immune 186880 to say: TCRαβ T-cell dysregulation autoimmunity, deficiency), impaired and diarrhea.

Tcellsproliferation JClinImmunol LCK deficiency Defects in LCK – aproximal AR Normal total numbers but CD4+ Normal Normal IgG and Diarrhea, recurrent infections, 615758 tyrosine kinase that interacts with T-cell lymphopenia, low IgA and increased immune dysregulation TCR Treg numbers, restricted IgM autoimmunity, 153390 Tcellrepertoireand impaired TCR signaling MALT1deficiency Mutationsin MALT1 – AR Normal Normal Bacterial, fungal and viral infections 615468 lnImmunol Clin J Table 1 (continued)

Disease Genetic defect/Presumed Inheritance Circulating T cells Circulating B cells Serum Ig Associated Features Phenotype pathogenesis OMIM Gene OMIM number

acaspase-likecysteineproteasethat Normal number but impaired Impaired antibody is essential for nuclear Tcellsproliferation response factor-kappa-B activation 604860 CARD11 deficiency Defects in CARD11 – acts as AR Normal predominance of naive Normal predominance Absent/low Pneumocystis jirovicii pneumonia, 615206 ascaffoldforNF-9B T-lymphocyte, impaired of transitional bacterial infections, activity in the adaptive Tcellsproliferation Blymphocytes, immune response 607210 BCL10 deficiency Mutations in BCL10 which AR Normal numbers, low memory Normal number; decreased Low Recurrent bacterial and 616098 encodes the B cell CLL / TandTregs,decreased memory and switched B viral infections, candidiasis, lymphoma 10 protein that proliferation to antigen and anti- cells gastroenteritis forms a heterotrimer with CD3 Malt1 and CARD family adaptors and plays a role in NF-kB signaling 603517 IL-21 deficiency Mutation in IL21 AR Normal number. Low IgG deficiency Severe early onset colitis 615767 605384 Normal/low function IL-21R deficiency Defects in IL21R – together with AR Abnormal T cell cytokine production; Normal Normal but impaired Suspectibility to cryptoporidia 615207 common gamma Abnormal T cell proliferation specific responses and pneumocystis and cholangitis chain binds IL-21 to specific stimuli 605383 OX40 deficiency Defects in OX40 (TNFRSF4) AR Normal T cell numbers; decreased Normal B cell numbers; Normal Kaposi’ssarcoma;impaired 615593 encoding a co-stimulatory antigen specific memory CD4+ reduced frequency of immunity to HHV8 molecule expressed on cells memory B cells activated T cells 600315 IKBKB deficiency Defects in IKBKB,encoding AR Normal total T cells; absent regulatory Normal B cell numbers; Decreased Recurrent bacterial, viral and f 615592 IkB 2 kinase 2, a and +% T cells; impaired TCR impaired BCR activation; ungal infections; clinical component of the NF-kB pathway activation phenotype of SCID 603258 LRBA deficiency Mutations in LRBA AR Normal or decreased CD4 numbers; Low or normal numbers of B Reduced I IgG Recurrent infections, inflammatory 614700 (lipopolysaccharide Tcelldysregulation cells and IgA in most bowel disease, autoimmunity; responsive beige-like EBV infections anchor protein) 606453 CD27 deficiency Mutations in CD27 (TNFRSF7) AR Normal No memory B cells Hypogamma- Clinical and immunologic features 615122 encoding TNF-R member globulinaemia triggered by EBV infection, HLH superfamily required for following EBV Aplastic anaemia, Lymphoma, generation and long-term infection hypogammaglobulinemia, maintenance of T cell immunity Low iNKT cells 186711 NIK deficiency Mutation in MAP3K14,encoding AR Normal number; impaired proliferation Decreased total peripheral Hypogamma- Recurrent bacterial, viral and Not yet NIK (NF-kB-inducing kinase) in response to antigen stimulation. Bcellandswitched globulinaemia Cryptosporidium infections. assigned 604655 Polycloncal Vβ repertoires memory B cells Low NK cell number and defective NK cell activation CTPS1 deficiency Mutation in CTPS1,encoding AR Normal or decreased number Normal/low number Normal/high IgG Recurrent/chronic viral infections 615897 CTP synthase 1, essential Normal or decreased proliferation specially EBV and VZV, for lymphocyte proliferation bacterial infections, EBV-driven 123860 B-cell non-Hodgkin lymphoma Table 1 (continued)

Disease Genetic defect/Presumed Inheritance Circulating T cells Circulating B cells Serum Ig Associated Features Phenotype pathogenesis OMIM Gene OMIM number

Omenn syndrome Hypomorphic mutations in RAG1, Present; restricted T cell repertoire Normal or decreased Decreased, except Erythroderma, , 603554 RAG2, Artemis, IL7RA, RMRP, and impaired function for increased IgE adenopathies, ADA, DNA Ligase IV, IL2RG, hepatosplenomegaly AK2,orassociatedwithDiGeorge syndrome; some cases have no defined gene mutation

Total no. of genes in Table 1:49 New genes added: DOCK2, B2M, IL21, MAP3K14, CTPS1 Notes: Infants with SCID who have maternal T cell engraftment may have allogeneic T cells present even in normal numbers, but that do not function normally; these cells may cause autoimmune cytopenias or graft versus host disease. Hypomorphic mutations in several of the genes that when affected by null mutations cause SCID may result in Omenn syndrome (OS), or “leaky” SCID or a less profound combined immunodeficiency or CID phenotype.BothOSandleakySCIDcanbeassociatedwith>300 autologous T cells/uL of peripheral blood and reduced rather than absent proliferative responses; Individuals with partially defective, or leaky, mutations are generally more mildly affected compared with those with typical SCID caused by null mutations. A spectrum of clinical findings including typical SCID, OS, leaky SCID, CID, granulomas with T lymphopenia, autoimmunity and CD4+ T lymphopenia can be found in an allelic series of RAG1 and other SCID associated genes. RAC2 deficiency is a disorder of leukocytemotilityandisreportedinTable5;however,onepatientwithRAC2deficiencyhadabsentTcellreceptorexcisioncircles(TRECs) by newborn screening, though T cell numbers and mitogen responses were not impaired. For additional syndromic conditions with T cell lymphopenia, such as DNA repair defects, cartilage hair hypoplasia, IKAROS deficiency and NEMO syndrome, see Tables 2 and 6;however,itshouldbenotedthatindividualswiththe most severe manifestations of these disorders could have clinical signs and symptoms of SCID UNC119 deficiency has been removed from this version of the classification tables, as the UNC119 variant reported previously has been identified as a polymorphism in unaffected individuals (Gorska MM, Alam R. A mutation in the human Uncoordinated 119 gene impairs TCR signaling and is associated with CD4 lymphopenia. Blood.2012Feb9;119(6):1399–406. doi: 10.1182/blood-2011-04- 350686.Epub2011Dec19).SeeErratum(Blood.2014Jan16;123(3):457) XL X-linked inheritance, AR autosomal recessive inheritance, AD autosomal dominant inheritance, SCID severe combined immune deficiency, EBV epstein barr virus, Ca++ calcium, MHC major histocompatibility complex, RTE recent thymic emigrants, HPV human papillomavirus JClinImmunol lnImmunol Clin J Table 2 Combined immunodeficiencies with associated or syndromic features

Disease Genetic defect/Presumed Inheritance Circulating T cells Circulating B Serum Ig Associated features OMIM pathogenesis cells number OMIM number gene locus Phenotype

1. Congenital thrombocytopenia Wiskott-Aldrich syndrome (WAS) Mutations in WAS;cytoskeletaland XL Progressive decrease, Abnormal Normal numbers Decreased IgM: antibody Thrombocytopenia with small platelets; 300392 immunologic synapse defect affecting lymphocyte responses to polysaccharides eczema; lymphoma; autoimmune haematopoietic to anti-CD3 particularly decreased; disease; IgA nephropathy; bacterial stem cell derivatives often increased and viral infections. XL 301000 IgA and IgE thrombocytopenia is a mild form of WAS, and XL neutropenia is caused by missense mutations in the GTPase binding domain of WASP WIP deficiency Mutations in WIPF1;cytoskeletal AR Reduced, Defective lymphocyte Low Normal, except for Recurrent infections; eczema; 614493 and immunologic synapse responses to anti-CD3 increased IgE thrombocytopenia. WAS-like phenotype. defect affecting haematopoietic stem cell derivatives 602357 2. DNA repair defects (other than those in Table 1) Ataxia-telangiectasia Mutations in ATM;disorderof AR Progressive decrease, abnormal Normal Often decreased IgA, Ataxia; telangiectasia; pulmonary 208900 cell cycle check-point proliferation to mitogens IgE and IgG infections; lymphoreticular and and DNA double- strand subclasses; increased other malignancies; increased break repair IgM monomers; alpha fetoprotein and increased 607585 antibodies variably radiosensitivity; chromosomal instability decreased Nijmegen breakage syndrome Hypomorphic mutations in NBS1 AR Progressive decrease Variably reduced Often decreased IgA, IgE Microcephaly; bird-like face; lymphomas; 251260 (Nibrin); disorder of cell cycle and IgG subclasses; solid tumors; increased radiosensitivity; checkpoint and DNA increased IgM; chromosomal instability double- strand break repair antibodies variably 602667 decreased Bloom syndrome Mutations in BLM (RECQL3); AR Normal Normal Reduced Short stature; bird like face; sun- 210900 encoding DNA helicase sensitive erythema; marrow RecQ protein-like 3 helicase failure; ; lymphoma; 604610 chromosomal instability Immunodeficiency with Mutations in DNA methyltransferase AR Decreased or normal; responses Decreased or normal Hypogammaglobulinemia; Facial dysmorphic features; 242860 centromeric instability DNMT3B (ICF1) resulting i to PHA may be decreased variable antibody deficiency macroglossia; bacterial/opportunistic and facial anomalies ndefectiveDNAmethylation602900; infections; malabsorption; cytopenias; (ICF1) malignancies; multiradial configurations of chromosomes 1, 9, 16; no DNA breaks Immunodeficiency with Mutations in ZBTB24 (ICF2) AR Decreased or normal; Decreased or normal Hypogammaglobulinemia; Facial dysmorphic features; macroglossia; 614069 centromeric instability 614064 Responses to PHA may variable antibody deficiency bacterial/opportunistic infections; and facial anomalies be decreased malabsorption; cytopenias; (ICF2) malignancies; multiradial configurations of chromosomes 1, 9, 16; PMS2 deficiency Mutations in PMS2,resultingi AR Normal Reduced B cells, Low IgG and IgA, Recurrent infections; café-au-lait 276300 nClassSwitchrecombination switched a elevated IgM, spots; lymphoma, colorectal deficiency due to impaired nd non-switched abnormal antibody carcinoma, brain tumor mismatch repair responses 600259 RNF168 deficiency Mutations in RNF168, AR Normal Normal Low IgG, IgM, or Short stature; mild defect of motor control 611943 resulting in defective DNA low IgA to ataxia; normal intelligence to double-strand learning difficulties; mild facial break repair (RIDDLE dysmorphism to microcephaly; syndrome) 612688 increased radiosensitivity MCM4 deficiency Mutations in MCM4 (minichromosome AR Normal Normal Normal Viral infections (EBV, HSV, VZV) 609981 maintenance complex component 4) Adrenal failure gene involved in DNA Short stature replication and repair Low NK cells Table 2 (continued)

Disease Genetic defect/Presumed Inheritance Circulating T cells Circulating B Serum Ig Associated features OMIM pathogenesis cells number OMIM number gene locus Phenotype

602638 3. Thymic defects with additional congenital anomalies DiGeorge syndrome* Contiguous gene deletion in De novo haplo-insufficiency Decreased or normal; 5 % have Normal Normal or decreased Hypoparathyroidism, conotruncal cardiac 188400 chromosome 22q11.2 or (majority) or AD; <1500 CD3 T cells/uL malformation, velopalatal insufficiency, mutation of a gene within phenocopies in neonatal period abnormal facies, intellectual disability this deletion region, TBX1, may have other as and other abnormalities; often with encoding a transcription yet undefined genetic lesions 3Mbinterstitialdeletionin22q11.2 factor critical for development (or rarely with intragenic mutation of of thymus and adjacent TBX1,deletionin10p) embryonic structures 602054 CHARGE syndrome Variable defects of the thymus De novo haplo-insufficiency Decreased or normal; Normal Normal or decreased Coloboma, heart anomaly, choanal atresia, 214800 due to CHD7 defects and associated T cell (majority) or AD response to PHA mental retardation, genital and ear abnormalities, often may be decreased anomalies; some are SCID-like and due to deletions or mutations have low TRECs in transcription regulator CHD7, 608892 CHARGE syndrome Variable defects of the thymus De novo haplo-insufficiency Decreased or normal; response Normal Normal or decreased Coloboma, heart anomaly, choanal atresia, 214800 due to SEMA3E defects and associated T cell abnormalities, (majority) or AD to mental retardation, genital and ear often due to deletions or PHA may be decreased anomalies; some are SCID-like mutations in transcription and have low TRECs regulator, or semaphorin SEMA3E 608166 Winged helix deficiency (nude) Defects in forkhead box N1 transcription AR Markedly decreased Normal Decreased Alopecia; nail dystropphy; severe infections 601705 AAB: syndromic SCID factor encoded abnormal thymic epithelium, by FOXN1 impaired T cell maturation 600838 4. Immune-osseous dysplasias Cartilage hair hypoplasia Mutations in RMRP (RNase AR Varies from severely decreased Normal Normal or reduced antibodies Short-limbed dwarfism with 250250 MRP RNA) Involved in (SCID) to normal; impaired variably decreased metaphysealdysostosis, processing of mitochondrial lymphocyte proliferation sparse hair, bone marrow failure, RNA and cell cycle control autoimmunity, susceptibility to 157660 lymphoma and other cancers, impaired spermatogenesis, neuronal dysplasia of the intestine Schimke Mutations in SMARCAL1; AR Decreased Normal Normal Short stature, spondiloepiphyseal dysplasia, 242900 Immunoosseous involved in chromatin remodeling intrauterine growth retardation, Dysplasia 606622 nephropathy; bacterial, viral, fungal infections; may present as SCID; bone marrow failure 5. Hyper-IgE syndromes (HIES) AD-HIES (Job or Buckley Syndrome) Dominant-negative heterozygous AD Normal overall Th-17 and Normal; reduced switched Elevated IgE; specific Distinctive facial features (broad nasal 147060 mutations in signal Often de novo T-follicular helper and non-switched antibody production bridge), bacterial infections (boils and transducer and activator mutation cells decreased memory B cells; BAFF decreased pulmonary abscesses, pneumatoceles) of transcription STAT3 expression increased due to S. aureus,aspergillus, 102582 Pneumocystis jirovecii;eczema, mucocutaneous candidiasis, hyperextensible joints, osteoporosis and bone fractures, scoliosis, retention of primary teeth, aneurysm formation JClinImmunol Comel-Netherton syndrome Mutations in SPINK5 resulting in AR Normal Switched and Elevated IgE and IgA Congenital ichthyosis, bamboo hair, 256500 lack of the serine protease non-switched Antibody variably decreased atopic diathesis, increased inhibitor LEKTI, expressed Bcellsarereduced bacterial infections, failure to thrive in epithelial cells 605010 PGM3 deficiency AR CD8 and CD4 T cells may Reduced B and memory 615816 be decreased Bcells lnImmunol Clin J Table 2 (continued)

Disease Genetic defect/Presumed Inheritance Circulating T cells Circulating B Serum Ig Associated features OMIM pathogenesis cells number OMIM number gene locus Phenotype

Mutations inphosphoglycomutase 3 Normal or elevated Severe atopy, autoimmunity, bacterial (PGM3) associated with a Ig’s, elevated IgE; and viral infections, cognitive glycosylationand atopy eosinophilia impairment, hypomyelination 172100 6. Dyskeratosis congenita (DKC) with bone marrow failure and dysfunctional telomere maintenance XL-DKC due to Dyskerin deficiency Mutations in DKC1 encoding XL Progressive decrease Progressive decrease Variable hypogammag- Intrauterine growth retardation, 305000 dyskerin lobulinemia microcephaly, nail dystrophy, 300126 recurrent infections, digestive tract involvement, pancytopenia, reduced number and function of NK cells. A severe phenotype with developmental delay and cerebellar hypoplasia is known as Hoyeraal- Hreidarsson Syndrome (HHS) AR-DKC due to nucleolar Mutations in NOLA2 (NHP2), AR Decreased Variable Variable Pancytopenia, sparse scalp hair and 613987 protein family A component of the H/ACA eyelashes, prominent periorbital member 2 (NHP2) deficiency ribonucleo-protein complex telangiectasia, hypoplastic/dysplastic nails 606470 AR-DKC due to nucleolar Mutation in NOLA3 (NOP10, AR Decreased Variable Variable Pancytopenia, sparse scalp hair and 224230 protein family A member 3 PCFT), a component eyelashes, prominent periorbital (NHP3) or NOP10 deficiency of the H/ACA ribonucleo- telangiectasia, hypoplastic/ protein complex dysplastic nails 606471 AR-DKC due to regulator of Mutation in RTEL1 encoding AD or AR Decreased Variable Variable Pancytopenia, sparse scalp hair and 615190 telomere elongation (RTEL1) regulator of telomere eyelashes, prominent periorbital deficiency elongation helicase telangiectasia, hypoplastic/dysplastic 1(RTEL1) nails. May present as HHS 608833 AD-DKC due to TERC Mutation in TERC encoding telomerase AD Variable Variable Variable Reticular hyperpigmentation of the skin, 127550 deficiency RNA component dystrophic nails, osteoporosis 602322 premalignant leukokeratosis of the oral mucosa, palmar hyperkeratosis, anemia, pancytopenia. May present as HHS AD-DKC due to TERT Mutation in TERT encoding AD or AR Variable Variable Variable Reticular hyperpigmentation of the 613989 deficiency telomerase reverse skin, dystrophic nails, osteoporosis transcriptase 187270 premalignant leukokeratosis of the oral mucosa, palmar hyperkeratosis, anemia, pancytopenia. AD version is milder than the AR version which can resemble HHS AD-DKC due to TINF2 Mutation in TINF2 encoding AD Variable Variable Variable Reticular hyperpigmentation of the 613990 deficiency telomerase interacting skin, dystrophic nails, osteoporosis factor 2 604319 premalignant leukokeratosis of the oral mucosa, palmar hyperkeratosis, anemia, pancytopenia. May present as HHS AD/AR -DKC due to TPP1 deficiency Mutation in adrenocortical dysplasia AD/AR Variable Variable Variable Reticular hyperpigmentation of the skin, homolog (ACD) encoding dystrophic nails, osteoporosis TPP1 affecting the TELpatch leukoplakia domain resulting in failure to of the oralmucosa, carcinoma, leukemia recruit telomerase to telomers palmar hyperkeratosis, anemia, 609377 pancytopenia. May present as HHS AR-DKC due to DCLRE1B Mutation in DCLRE1B/ SNM1/ AR dyskeratosis congenita and 616353 deficiency APOLLO: DNA Hoyeraal-Hreidarsson CROSS-LINK REPAIR (HH) syndrome PROTEIN 1B 609683 AR 616353 Table 2 (continued)

Disease Genetic defect/Presumed Inheritance Circulating T cells Circulating B Serum Ig Associated features OMIM pathogenesis cells number OMIM number gene locus Phenotype

AR-DKC due to PARN Mutation in PARN, POLYADENYLATE- deficiency SPECIFIC RIBONUCLEASE 604212 7. Defects of Vitamin B12 and Folate metabolism Transcobalamin 2 Mutation in TCN2;encodinga AR Normal Variable Decreased Megaloblastic anaemia, 275350 (TCN2) deficiency transporter of cobalamin into pancytopaenia, if untreated blood cells for prolonged periods results 613441 in mental retardation SLC46A1/PCFT deficiency Mutation in SLC46A1, AR Variable numbers and Variable Decreased Megaloblastic anaemia, failure to 229050 causing hereditary encoding a proton activation profile thrive, if untreated f 611672 folate malabsorbtion coupled folate transporter or prolonged periods results in mental retardation Methylene-tetrahydrofolate Mutations in enzyme encoded by AR Low Low Decreased Megaloblastic anaemia, failure 601634 dehydrogenase MTHFD,essentialfor to thrive, neutropenia, s 172460 1(MTHFD1)deficiency processing single-carbon eizures, mental retardation folate derivatives 8. Anhidrotic ectodermaldysplasia with immunodeficiency (EDA-ID) (EDA-ID. NEMO /IKBKG deficiency Mutations of NEMO (IKBKG), XL Normal or decreased; Normal Decreased; poor specific anhidrotic ectodermal dysplasia 300291, amodulatorofNF-κBactivation poor CR activation Low B memory B cells antibody responses, +specificantibodydeficiency 300584, Defects in IKBKG,encodingNEMO, function absent antibody to (lack of Ab response to polysac- 300301 acomponentoftheNF-κBpathway polysaccharide antigens charides) + various infections 300640 Mutations of NEMO (IKBKG), (mycobacteria and pyogens) amodulatorofNF-κBactivation Various infections (bacteria, 300248 mycobacteria, viruses and fungi); colitis, EDA (not in all patients); conical teeth, variable defects of skin pigmentation, dysfunction EDA-ID IKBA gain Gain of function mutation in IKBA AD Normal total T cells;; Normal B cell numbers; Decreased; poor specific Various infections (bacteria, 612132 of function mutation (NFKIAB),encodingIκBα,a impaired impaired BCR antibody responses, mycobacteria, viruses and fungi); component of the NF-κB TCR activation activation; absent antibody to colitis, EDA (not in all patients); pathway polysaccharide antigens variable defects of skin, hair and teeth, Gain-of-function mutation of Tcellandmonocytedysfunction IKBA,resultinginimpaired Anhidrotic ectodermal dysplasia + T cell activation of NF-κB defect + various infections: Recurrent 164008 bacterial, viral and fungal infections; 9. Calcium channel defects ORAI-I deficiency Mutation in ORAI1,aCa++ AR Normal; defective TCR Normal Normal Autoimmunity, anhydrotic ectodermic 612782 release-activated channel mediated activation dysplasia, non-progressive myopathy (CRAC) modulatory component 610277 STIM1 deficiency Mutations in STIM1,astromal AR Normal; defective TCR Normal Normal Autoimmunity, anhydrotic ectodermal 612783 interaction molecule 1 mediated activation dysplasia, non-progressive myopathy 605921 10. Other defects Hepatic veno-occlusive disease Mutations in nuclear body AR Normal (decreased Normal (decreased Decreased IgG, IgA, Hepatic veno-occlusive disease; 235550 with immunodeficiency protein encoded by SP110 memory T cells) memory B cells) IgM; absent germinal Susceptibility to Pneumocystis

(VODI) 604457 centers and tissue jiroveci pneumonia, CMV, candida; JClinImmunol plasma cells thrombocytopenia; hepatosplenomegaly; cerebrospinal leukodystropy Facial dysmorphism, Mutation in POLE1; AR Low naïve T cells; decreased Low memory B cells Decreased IgM and Mild facial dysmorphism (malar hypoplasia, 615139 immunodeficiency, Defective DNA replication Tcellproliferation IgG; Lack of antibodies high forehead), livedo, short stature; livedo, short stature 174762 to polysaccharide recurrent upper and lower respiratory (FILS) syndrome antigens tract infections, recurrent pulmonary infections and recurrent meningitis lnImmunol Clin J Table 2 (continued)

Disease Genetic defect/Presumed Inheritance Circulating T cells Circulating B Serum Ig Associated features OMIM pathogenesis cells number OMIM number gene locus Phenotype

Immunodeficiency with Mutation in TTC7A (tetratricopeptide AR Variable, but sometimes absent Normal Decreased Multiple intestinal atresias, often with 243150 multiple intestinal atresias repeat (TPR) domain 7A) protein, intrauterine polyhydramnios and of unkown function early demise; some with SCID 609332 phenotype Vici syndrome due to Mutations in EPG5 encoding ectopic AR Profound depletion of CD4+ Defective Decreased (particularly IgG2) Agenesis of the corpus callosum, cataracts, 242840 EPG5 deficiency P-granules autophagy protein cells cardiomyopathy, skin hypopigmentation, 615068 5, involved in the formation of cleft lip/palate, recurrent infections, autolysosomes required for autophagy chronic mucocutaneous candidiasis Purine nucleoside phosphorylase Mutation of PNP leading to absent AR Progressive decrease Normal Normal or decreased Autoimmune haemolytic anemia, 613179 (PNP) deficiency PNP, T cell and neurologic neurological impairment defects from elevated toxic metabolites, especially dGTP 164050 HOIL1 deficiency Mutation of HOIL1/RBCK1, AR Normal numbers, Normal, but decreased Poor antibody production Bacterial infections (pyogens), 615895 encoding a component of the memory B cells to polysaccharide autoinflammation. amylopectinosis linear ubiquitination chain antigens assembly complex LUBAC, resulting in impaired activation of NF-κB 610924 HOIP deficiency Mutation of HOIP1 (/RNF31), AR Normal numbers Normal, but decreased decreased Bacterial infections (pyogens), Not yet encoding a component of the memory B cells autoinflammation. Amylopectinosis, assigned linear ubiquitination chain Lymphangiectasia assembly complex LUBAC, resulting in impaired activation of NF-κB 612487 Hennekam-lymphangiectasia- Mutation of CCBE1:(COLLAGEN AR Low/variable Low/variable decreased Lymphangiactasia and lymphedema with 235510 lymphedema syndrome AND CALCIUM-BINDING facial abnormalities and other EGF DOMAIN- dysmorphic features CONTAINING PROTEIN1) 612753 STAT5b deficiency Mutations in STAT5B signal AR Modestly decreased Normal Normal Growth-hormone insensitive dwarfism, 245590 transducer and transcription dysmorphic features, eczema, factor, essential for normal lymphocytic interstitial pneumonitis, signaling from IL-2 and autoimmunity 15, key growth factors for T and NK cells, as well as other cytokines 604260

Total no. of genes in Table 2:45 New genes added: TPP1, DCLRE1B, PARN, CCBE1, HOIP1, EPG5 Notes: T and B cell number and function in these disorders exhibit a wide range of abnormality; the most severely affected cases meet diagnostic criteria for SCID or leaky SCID and require immune system restoring therapy such as allogeneic hematopoietic cell transplantation *AlthoughTBX1deletionsareemphasized,dataarelacking that demonstrate that isolated TBX1 haploinsufficiency (affecting solely the gene and none of the surrounding 22q11.2 region) explicitly causes Tcellorimmunologicdeficiencyinhumans Table 3 Predominantly antibody deficiencies

Disease Genetic defect/Presumed pathogenesis Inheritance Serum Ig Associated features Phenotype Gene OMIM OMIM number 1. Severe reduction in all serum immunoglobulin isotypes with profoundly decreased or absent B cells BTK deficiency Mutations in BTK,acytoplasmictyrosinekinase XL All isotypes decreased in majority Severe bacterial infections; normal 300755 activated by crosslinking of the BCR of patients; some patients have numbers of pro-B cells 300300 detectable immunoglobulins μ heavy chain deficiency Mutations in μ heavy chain (IGHM); essential AR All isotypes decreased Severe bacterial infections; normal 601495 component of the pre-BCR numbers of pro-B cells 147020 λ5 deficiency Mutations in λ5(IGLL1); part of the surrogate AR All isotypes decreased Severe bacterial infections; normal 613500 light chain in the pre-BCR numbers of pro-B cells 146770 Igα deficiency Mutations in Igα (CD79A); part of the pre-BCR AR All isotypes decreased Severe bacterial infections; normal 112205 and BCR 112205 numbers of pro-B cells 613501 Igβ deficiency Mutations in Igb (CD79B); part of the pre-BCR AR All isotypes decreased Severe bacterial infections; normal 612692 and BCR numbers of pro-B cells 147245 BLNK deficiency Mutations in BLNK; a scaffold protein that AR All isotypes decreased Severe bacterial infections; normal 613502 binds to BTK 604615 numbers of pro-B cells PI3KR1 deficiency Mutations in PIK3R1; akinaseinvolvedin AR All isotypes decreased Severe bacterial infections; decreased 615214 signal transduction in multiple cell types. or absent pro-B cells Complete loss of PI3K p85-alpha resulting in complete loss of B cell development 171833 E47 transcription factor deficiency Mutations in TCF3;atranscriptionfactor AD All isotypes decreased Recurrent bacterial infections Not yet assigned required for control of B cell development 147141 Thymoma with immunodeficiency Unknown None One or more isotypes may Bacterial and opportunistic infections; be decreased autoimmunity; decreased number of pro-B cells Disease Genetic defect/Presumed pathogenesis Inheritance Serum Ig Associated features OMIM number 2. Severe reduction in at least 2 serum immunoglobulin isotypes with normal or low number of B cells Common variable immuno- Unknown Variable Low IgG and IgA and/or IgM Clinical phenotypes vary: most have recurrent deficiency disorders infections, some have polyclonal lymphoproliferation, autoimmune cytopenias and/or granulomatous disease CD19 deficiency Mutations in CD19;transmembraneproteinthat AR Low IgG and IgA and/or IgM Recurrent infections; May have glomerulonephritis 613493 amplifies signal through BCR 107265 CD81 deficiency Mutations in CD81;transmembraneprotein AR Low IgG, low or normal IgA and IgM Recurrent infections; May have glomerulonephritis 613496 that amplifies signal through BCR 186845 CD20deficiency Mutations in CD20; a B cell surface receptor AR Low IgG, normal or elevated IgM and IgA Recurrent infections 613495 involved in B cell development and plasma cell differentiation 112210 CD21 deficiency Mutations in CD21; also known as complement AR Low IgG; impaired anti-pneumococcal Recurrent infections 614699 receptor 2 and forms part of the CD19 complex response 120650 TACI deficiency Mutations in TNFRSF13B (TACI); a TNF receptor AD or AR or complex Low IgG and IgA and/or IgM Variable clinical expression 240500 family member found on B cells and is a receptor for BAFF and APRIL 604907 BAFF receptor deficiency Mutations in TNFRSF13C (BAFF-R); a TNF AR Low IgG and IgM; Variable clinical expression 613494 receptor family member found on B cells and is a receptor for BAFF 606269 TWEAK deficiency Mutations in a cytokine TWEAK (TNFSF12); AD Low IgM and A; lack of anti- Pneumonia, bacterial infections, warts; not yet assigned JClinImmunol TNF-related weak inducer of apoptosis pneumococcal antibody thrombocytopenia. neutropenia 602695 NFKB2 deficiency Mutations in NFKB2;anessentialcomponent AD Low IgG and IgA and IgM; very Recurrent infections; adrenal 615577 of the noncanonical NF-κBpathway low B cells in some insufficiency; ACTH deficiency; alopecia MOGS deficiency Mutation in mannosyl-oligosaccharide glucosidase AR Severe hypogammaglobulinemia; Bacterial and viral infections; severe neurologic 606056 601336 disease; also contains glycosylation type IIb (CDG-IIb), lnImmunol Clin J Table 3 (continued) TRNT1 deficiency Mutation in TRNT1 a template- AR B cell deficiency and congenital sideroblastic anemia; 616084 independent RNA polymerase required hypogammaglobulinemia deafness; for the maturation of cytosolic and developmental delay mitochondrial transfer RNAs (tRNAs) 612907 TTC37 deficiency Mutation in TTC37 gene AR Poor antibody response to Recurrent bacterial and viral infections; 222470 614589 pneumococcal vaccine Abnormal hair findings: trichorrhexis nodosa 3. Severe reduction in serum IgG and IgA with normal/elevated IgM and normal numbers of B cells AID deficiency Mutations in AICDA gene AR IgG and IgA decreased; IgM Bacterial infections; enlarged lymph 605258 605257 increased nodes and germinal centers UNG deficiency Mutations in UNG AR IgG and IgA decreased; IgM Enlarged lymph nodes and germinal 608106 191525 increased centers INO80 INO80 chromatin remodeling AR IgG and IgA decreased; IgM Severe bacterial infections not yet complex; mild DNA repair increased assigned defect 610169 MSH6 MSH6 gene defect part of mismatch AR Variable IgG, defects; increased Family or personal history of cancer not yet repair [MMR] machinery); DNA IgM in assigned repair defect some; normal B cells, low switched 600678 memory B cells; Ig-CSR and SHM defects 4. Isotype or light chain deficiencies with generally normal numbers of B cells Activated PI3K-δ Mutation in PIK3CD; p110 AD gain of Reduced IgG2 and impaired Respiratory infections, bronchiectasis; 615513 encoding for p110 subunit of PI3K function antibody autoimmunity; chronic EBV, 602839 to pneumococci and hemophilus CMV infection PI3KR1 loss of function Mutation in PIK3R1 leading to AD loss of Absent IgA, low IgG EBV, CMV viremia; growth 616005 mutations in p85α function retardation 171833 of p85α (leading to activation of PI3K-δ – as above) Ig heavy chain mutations Mutation or chromosomal deletion at AR One or more IgG and/or IgA May be asymptomatic and deletions 14q32 subclasses as well as IgE may be absent IGKC deficiency Mutations in Kappa constant gene AR All immunoglobulins have lambda Asymptomatic 147200 light chain Isolated IgG subclass Unknown Variable Reduction in one or more IgG Usually asymptomatic; a minority may deficiency subclass have poor antibody response to specific antigens and recurrent viral/bacterial infections IgA with IgG subclass Unknown Variable Reduced IgA with decrease in one Recurrent bacterial infections deficiency or more IgG subclass Specific antibody Unknown Variable Normal Reduced ability to produce antibodies deficiency with normal Ig to specific antigens concentrations and normal numbers of B cells Table 3 (continued) Transient Unknown Variable IgG and IgA decreased Normal ability to produce antibodies hypogammaglobulinemia to vaccine antigens, usually not of infancy with normal associated with significant numbers of B cells infections CARD 11 gain of function CARD11; scaffold for NF-kB activity AD Congenital B cell lymphocytosis. Splenomegaly; lymphadenopathy 607210; in the adaptive immune response; gain of High B cell numbers due to 606445 function constitutive NF-κBactivation

Total no. of gene in Table 3:28 New genes added: MOGS, TRNT1, TTC37, IN08, MSH6, PI3KR1 AD Notes: Several autosomal recessive disorders that might previously have been called CVID have been added to Table 3.CD81isnormallyco-expressedwithCD19 on the surface of B cells. As for CD19 mutations, mutations in CD81 result in normal numbers of peripheral blood B cells, low serum IgG and an increased incidence of glomerulonephritis Common Variable Immunodeficiency Disorders (CVID)includeseveralclinicalandlaboratoryphenotypes that may be caused by distinct genetic and/orenvironmentalfactors.Some patients with CVID and no known genetic defect have markedly reduced numbers of B cells as well as hypogammaglobulinemia. Alterations in TNFRSF13B (TACI) and TNFRSF13C (BAFF-R) sequences may represent disease modifying mutations rather than disease causing mutations. A small minority of patients with XLP (Table 4), WHIM syndrome (Table 6), ICF (Table 2), VOD1 (Table 2), thymoma with immunodeficiency (Good syndrome) or myelodysplasia are first seen by an immunologist because of recurrent infections, hypogammaglobulinemia and normal or reduced numbers of B cells XL X-linked inheritance, AR autosomal recessive inheritance, AD autosomal dominant inheritance;BTKBruton tyrosine kinase, BLNK Bcelllinkerprotein AID activation-induced cytidine deaminase, UNG uracil-DNA glycosylase, Ig(κ) immunoglobulin or κ light-chain type JClinImmunol lnImmunol Clin J Table 4 Diseases of immune dysregulation

Disease Genetic defect/Presumed Inheritance Circulating T Cells Circulating B Functional defect Associated Features Phenotype pathogenesis cells OMIM Gene OMIM number

1. Familial hemophagocytic lymphohistiocytosis (FHL) syndromes 1.1. FHL syndromes without hypopigmentation Perforin deficiency (FHL2) Mutations in PRF1;perforinis AR Increased activated T cells Normal Decreased to absent NK and CTL Fever, Hepato-Splenomegaly (HSMG), 603553 amajorcytolyticprotein activities cytotoxicity Hemophagocytic lymphohistiocytosis 170280 (HLH), Cytopenias (UNC13D / Munc13-4 Mutations in UNC13D;required AR Increased activated T cells Normal Decreased to absent NK and CTL Fever, HSMG, HLH, Cytopenias, 608898 deficiency (FHL3) to prime vesicles for fusion activities 608897 (cytotoxicity and/or degranulation) Syntaxin 11 deficiency, (FHL4) Mutations in STX11, required for AR Increased activated T cells Normal Decreased NK activity (cytotoxicity Fever, HSMG, HLH, Cytopenias, 603552 secretory vesicle fusion and/or degranulation) with the cell membrane 605014 STXBP2 / Munc18-2 deficiency Mutations in STXBP2,required AR or AD Increased activated T cells Normal Decreased NK and CTL activities Fever, HSMG, HLH, Cytopenias, 613101 (FHL5) for secretory vesicle fusion (cytotoxicity and/or degranulation) with the cell membrane 601717 SH2D1A deficiency (XLP1) Mutations in SH2D1A encoding XL Normal or increased activated Reduced Memory partially defective NK cell and CTL Clinical and immunologic features triggered by EBV 308240 an adaptor protein regulating Tcells Bcells cytotoxic activity infection: HLH, lymphoproliferation, Aplastic intracellular signaling anaemia, lymphoma. 300490 Hypogammaglobulinemia, absent iNKT cells XIAP deficiency (XLP2) Mutations in XIAP/ BIRC4 XL Normal or Increased activated Normal or Increased T cells susceptibility to apoptosis EBV infection, Splenomegaly, lymphoproliferation 300635 encoding Tcells;low/normaliNKT reduced to CD95 and enhanced activation- HLH, Colitis, IBD, hepatitis an inhibitor of apoptosis cells Memory B induced cell death (AICD) Low iNKT cells 300079 cells 1.2. FHL syndromes with hypopigmentation Chediak-Higashi syndrome Mutations in LYST,impaired AR Increased activated T cells Normal Decreased NK and CTL activities Partial albinism, recurrent infections, fever, 214500 lysosomal trafficking (cytotoxicity HSMG, HLH 606897 and/or degranulation) Giant lysosomes, neutropenia, cytopenias, bleeding tendency, progressive neurological dysfunction Griscelli syndrome, type2 Mutations in RAB27A encoding AR Normal Normal Decreased NK and CTL activities Partial albinism, fever, HSMG, HLH, cytopenias 607624 a GTPase that promotes (cytotoxicity docking of secretory vesicles to and/or degranulation) the cell membrane 603868 Hermansky-Pudlak syndrome, Mutations in AP3B1 gene, AR Normal Normal Decreased NK and CTL activities Partial albinism, recurrent infections, 608233 type 2 encoding for the β subunit of (cytotoxicity pulmonary fibrosis the AP-3 complex and/or degranulation) Increased bleeding, neutropenia, HLH 603401 Hermansky-Pudlak syndrome, Mutations in PLDN,encoding AR (Not assessed; ) (Not assessed, Decreased NK cell cytolytic activity Oculocutaneous albinism, recurrent cutaneous 614171 type 9 Pallidin, a component of the leukopenia) infections, leukopenia, thrombocytopenia biogenesis of lysosome-related organelles complex-1 (BLOC- 1) 604310 2. T regulatory cells genetic defects IPEX, immune dysregulation, Mutations in FOXP3,encoding XL Normal Normal Lack of (and/or impaired function of) Autoimmune enteropathy, early onset diabetes, 304790 polyendocrinopathy, aTcelltranscriptionfactor CD4+ CD25+ FOXP3+ thyroiditis hemolytic anemia, enteropathy X-linked 300292 regulatory T cells (Tregs) thrombocytopenia, eczema Elevated IgE, IgA CD25 deficiency Mutations in IL2RA,encoding AR Normal to decreased Normal No CD4 + C25+ cells with impaired f Lymphoproliferation, autoimmunity. 606367 IL-2Rα chain, 147730 unction of Tregs cells Impaired T cell proliferation CTLA4 deficiency (ALPSV) Mutations in CTLA4,encoding AD Decreased Decreased Impaired function of Treg cells. Autoimmune cytopenias, enteropathy, 616100 Cytotoxic T Lymphocyte interstitial lung disease, antigen 4, a protein that Table 4 (continued)

Disease Genetic defect/Presumed Inheritance Circulating T Cells Circulating B Functional defect Associated Features Phenotype pathogenesis cells OMIM Gene OMIM number

negatively regulate T cell extra-lymphoid lymphocytic infiltration recurrent receptor signaling and infections, Tcellactivation. 123890 STAT3 GOF mutations Mutations in STAT3,encoding AD Decreased Decreased Enhanced STAT3 signaling, leading to Lymphoproliferation, Solid organ autoimmunity, 615952 Signal Transducer and activator increased Th17 cell differentiation, recurrent infections. 3 lymphoproliferation and autoimmunity. 102582 Decreased Treg cell numbers and impaired phenotype 3. Autoimmunity with or without lymphoproliferation APECED (APS-1), autoimmune Mutations in AIRE,encodinga AR Normal Normal AIRE-1 serves as check-point in the Autoimmunity: hypoparathyroidism hypothyroidism, 240300 polyendocrinopathy transcription regulator needed thymus for negative selection of adrenal insufficiency, diabetes, gonadal dysfunction with candidiasis and ectodermal to establish thymic self- autoreactive T cells and for and other endocrine abnormalities, chronic dystrophy tolerance generation of Tregs mucocutaneous candidiasis, dental enamel 607358 hypoplasia, alopecia areata Enteropathy, Pernicious anemia, ITCH deficiency Mutations in ITCH,anE3 AR Not assessed Not assessed Itch deficiency may cause immune Early-onset chronic lung disease (interstitial 613385 ubiquitin ligase catalyzes the dysregulation by affecting both anergy pneumonitis) transfer of ubiquitin to a induction in auto-reactive effector T Autoimmune disorder (thyroiditis, type I diabetes, signaling proteins cells and generation of Tregs chronic diarrhea/enteropathy, and hepatitis) in the cell including Failure to thrive, developmental delay, dysmorphic phospholipase facial features Cγ1(PLCγ1) 606409 Tripeptidyl-Peptidase II Deficiency Mutations in TPP2,encoding AR Decreased Decreased TPP2 deficiency results in premature Variable lymphoproliferation, severe autoimmune Not yet tripeptidyl- immunosenescence and immune cytopenias, hypergammaglobulinemia, recurrent assigned peptidase II, serine dysregulation infections, exopeptidase involved in extralysosomal peptide degradation 190470 3. Autoimmune lymphoproliferative syndrome (ALPS) ALPS-FAS Germinal mutations in TNFRSF6, AD Increased CD4−CD8−TCRαβ Normal, low Apoptosis defect FAS mediated Splenomegaly, adenopathies, Autoimmune cytopenias, 601859 encoding CD95/Fas cell AR*** double negative (DN) T memory B increased lymphoma risk. surface apoptosis cells cells IgG and A normal or increased receptor** Elevated FasL and IL-10, vitamin B12 134637 ALPS-FASLG Mutations in TNFSF6,Fasligand AR Increased DN T cells Normal Apoptosis defect FAS mediated Splenomegaly, adenopathies, autoimmune cytopenias, 601859 for CD95 apoptosis SLE; 134638 Soluble FasL is not elevated ALPS-Caspase10 Mutations in CASP10,intracellular AD Increased DN T cells Normal Defective lymphocyte apoptosis Adenopathies, splenomegaly, autoimmunity. 603909 apoptosis pathway 601762 ALPS-Caspase 8 Mutations in CASP8,intracellular AR Slightly increased DN T cells Normal Defective lymphocyte apoptosis and Adenopathies, splenomegaly, Bacterial and viral 607271 apoptosis and activation activation infections, pathways Hypogammaglobulinemia 601763 FADD deficiency Mutations in FADD encoding an AR Increased DN T cells Normal Defective lymphocyte apoptosis Functional hyposplenism, 613759 adaptor molecule interacting Bacterial and viral infections, with FAS, and promoting Recurrent episodes of encephalopathy and liver JClinImmunol apoptosis dysfunction. 602457 PRKC delta deficiency Mutations in PRKCD, AR Normal Low memory B Apoptotic defect in B cells Recurrent infections; EBV chronic infection 615559 encoding a member of the protein cells and Lymphoproliferation kinase Elevation of CD5 SLE-like autoimmunity (Nephrotic and Cfamilycriticalforregulation Bcells antiphospholipid syndromes) lnImmunol Clin J Table 4 (continued)

Disease Genetic defect/Presumed Inheritance Circulating T Cells Circulating B Functional defect Associated Features Phenotype pathogenesis cells OMIM Gene OMIM number

of cell survival, proliferation HypoIgG and apoptosis 176977 4. Immune dysregulation with colitis IL-10 deficiency Mutations in IL10, AR Normal Normal No functional IL-10 secretion Inflammatory bowel disease (IBD) Folliculitis, not assigned encoding IL-10 Recurrent respiratory diseases, 124092 Arthritis, IL-10Rα deficiency Mutations in IL10RA, AR Normal Normal Leukocytes no response IBD, Folliculitis, 613148 encoding IL-10R1 to IL-10 Recurrent respiratory diseases, 146933 Arthritis, Lymphoma IL-10Rβ deficiency Mutations in IL10RB, AR Normal Normal Leukocytes no response IBD, Folliculitis, 612567 encoding IL-10R2 to IL-10, IL-22, IL-26, IL-28A, IL-28B, Recurrent respiratory diseases, 123889 and IL-29 Arthritis, Lymphoma NFAT5 haploinsufficiency Hemizygous deletion of NFAT5 AD Normal Normal Decreased memory B cells and IBD, recurrent sinopulmonary infections Not yet 604708 plasmablasts assigned 5. Type 1 Interferonopathies TREX1 deficiency, Aicardi- Mutations in TREX1,encoding AR Not assessed Not assessed Intracellular accumulation of abnormal Progressive encephalopathy Intracranial calcifications, 225750 Goutieres nuclease involves in clearing AD***** single-stranded (ss) DNA species Cerebral atrophy, leukodystrophy, cellular nucleic debris leading to increased CSF alpha-IFN HSMG, Thrombocytopenia, syndrome 1 (AGS1) 606609 production Elevated hepatic transaminases Chronic cerebrospinal fluid (CSF) lymphocytosis RNASEH2B deficiency, AGS2 Mutations in RNASEH2B, AR Not assessed Not assessed Intracellular accumulation of abnormal Progressive encephalopathy Intracranial calcifications, 610181 encoding nuclease subunit ss-DNA species leading to increased Cerebral atrophy, leukodystrophy, involves in clearing CSF alpha-IFN production HSMG, thrombocytopenia, cellular nucleic debris Elevated hepatic transaminases 610326 Chronic CSF lymphocytosis RNASEH2C deficiency, AGS3 Mutations in RNASEH2C, AR Not assessed Not assessed Intracellular accumulation of abnormal Progressive encephalopathy Intracranial calcifications, 610329 encoding nuclease subunit ss-DNA species leading to increased Cerebral atrophy, leukodystrophy, involves in clearing CSF alpha-IFN production HSMG, thrombocytopenia, cellular nucleic debris Elevated hepatic transaminases 610330 Chronic CSF lymphocytosis RNASEH2A deficienc y, AGS4 Mutations in RNASEH2A, AR Not assessed Not assessed Intracellular accumulation of abnormal Progressive encephalopathy Intracranial calcifications, 610333 encoding nuclease subunit ss-DNA species leading to increased Cerebral atrophy, leukodystrophy, involves in clearing CSF alpha-IFN production HSMG, thrombocytopenia, cellular nucleic debris Elevated hepatic transaminases 606034 Chronic CSF lymphocytosis SAMHD1 deficiency, AGS5 Mutations in SAMHD1,encoding AR Not assessed Not assessed Induction of the cell intrinsic antiviral Progressive encephalopathy Intracranial calcifications, 612952 negative regulator of the response, apoptosis, and Cerebral atrophy, leukodystrophy, immunostimulatory mitochondrial DNA destruction HSMG, thrombocytopenia, anemia elevated lactates DNA response leading to increased CSF alpha-IFN Chronic CSF lymphocytosis, 606754 production Skin vascularitis, mouth ulcers, arthropathy ADAR1 deficiency, AGS6 Mutations in ADAR1,encodinga AR Not assessed Not assessed Catalyzes the deamination of adenosine to Progressive encephalopathy intracranial calcification, 615010 RNA-specific adenosine inosine in dsRNA substrates Markedly Severe developmental delay, leukodystrophy deaminase elevated CSF IFN-alpha 146920 Aicardi-Goutieres syndrome 7 IFIH1 AD Not assessed Not assessed IFIH1 gene encodes a cytoplasmic viral Progressive encephalopathy intracranial calcification, 615846 (AGS7) 606951 RNA receptor that activates type I Severe developmental delay, leukodystrophy interferon signaling through the MAVS adaptor molecule Spondyloenchondro-dysplasia with Mutations in ACP5,encoding AR Not assessed Not assessed Upregulation of IFN-alpha and type I IFN- Recurrent bacterial and viral infections, 607944 immune tartrate-resitant acid stimulated genes Intracranial calcification, dysregulation (SPENCD) phosphatase SLE-like autoimmunity (Sjögren’ssyndrome, (TRAP) hypothyroidism, inflammatory myositis, 171640 Raynaud’s disease and vitiligo), hemolytic anemia, thrombocytopenia, Table 4 (continued)

Disease Genetic defect/Presumed Inheritance Circulating T Cells Circulating B Functional defect Associated Features Phenotype pathogenesis cells OMIM Gene OMIM number

skeletal dysplasia, short stature STING–associated vasculopathy, TMEM173 encoding for AR Not assessed Not assessed STING activates both the NF-kappa-B and Severe infantile-onset autoinfammatory vasculopathy, 615934 infantile- STIMULATOR IRF3 transcription pathways to induce onset OF INTERFERON GENES expression of IFN-alpha and IFN-beta 612374 and exert a potent antiviral effect ADA2 deficiency Mutations in CECR1; encoding AR Not assessed Not assessed ADAs deactivate extracellular adenosine Polyarteritis nodosa, childhood-onset, early-onset 615688 ADA2 and terminate signaling through recurrent ischemic stroke and fever 607575 adenosine receptors

Total no. of genes in Table 4:37 New genes added: PLDN, CTLA4, TPP2, NFAT5, IFIH1, TMEM173, CECR1, STAT 3 (GOF) XL X-linked inheritance, AR autosomal recessive inheritance, AD autosomal dominant inheritance, FHL familial hemophagocytic lymphohistiocytosis, HLH Hemophagocytic lymphohistiocytosis, HSMG hepato-splenomegaly, DN double-negative, SLE systemic lupus erythematous, IBD inflammatory bowel disease, CSF chronic cerebrospinal fluid ** Somatic mutations of TNFRSF6 cause a similar phenotype (ALPS-sFAS) see Table 9.Germinalmutationandsomatic mutations of TNFRSF6 can be associated in some ALPS-FAS patients *** AR ALPS-FAS patients have a most severe clinical phenotype **** Somatic mutations in KRAS or NRAS can give this clinical phenotype associated auto-immune leukoproliferative disease (RALD) and are now includeinTable9 entitled Phenocopies of PID ***** de novo dominant TREX1 mutations have been reported JClinImmunol lnImmunol Clin J Table 5 Congenital defects of phagocytenumber,function,orboth

Disease Genetic defect/ Inheritance Affected cells Affected function Associated features Phenotype Presumed pathogenesis OMIM number OMIM gene 1) Congenital neutropenias Elastase deficiency (SCN1) Mutation in ELANE: misfolded AD N Myeloid differentiation Susceptibility to MDS/leukemia 202700 protein response, increased apoptosis 130130 GFI 1 deficiency (SCN2) Mutation in GFI1:lossofrepression AD N Myeloid differentiation B/T lymphopenia 613107 of ELANE 600871 Kostmann Disease (SCN3) Mutation in HAX1:controlofapoptosis AR N Myeloid differentiation Cognitive and neurological 610738 605998 defects in patients with defects in both HAX1 isoforms, susceptibility to MDS/leukemia G6PC3 deficiency (SCN4) Mutation in G6PC3:abolishedenzymatic AR N+F Myeloid differentiation, Structural heart defects, urogenital 612541 activity of glucose-6-phosphatase, , abnormalities, − aberrant glycosylation, and enhanced O2 production inner ear deafness, and venous apoptosis of N and F angiectasias of trunks and limbs 611045 VPS45 deficiency (SCN5) Mutation in VPS45 controls AR N+F Myeloid differentiation, Extramedullary hematopoiesis, 615285 vesicular trafficking migration bone marrow fibrosis, nephromegaly, 610035 Glycogen storage disease Mutation in G6PT1: Glucose-6- AR N+M Myeloid differentiation, Fasting hypoglycemia, lactic acidosis, 232220 type 1b phosphate transporter 1 chemotaxis, hyperlipidemia, hepatomegaly − 602671 O2 production Mutation in ELANE:misfolded AD N Differentiation Oscillations of other leukocytes 162800 protein response and platelets 130130 X-linked neutropenia/ Mutation in WAS: Regulator of XL, gain of function N+M Mitosis 300299 myelodysplasia actin cytoskeleton (loss of autoinhibition) 300392 P14/LAMTOR2 deficiency Mutation in ROBLD3/LAMTOR2: AR N+L Endosome biogenesis Neutropenia 610798 Endosomal adaptor protein 14 Mel Hypogammaglobulinemia 610389 ↓CD8 cytotoxicity Partial albinism Growth failure Barth Syndrome Mutation in Tafazzin (TAZ)gene: XL N Myeloid differentiation Cardiomyopathy, myopathy, 302060 Abnormal lipid structure of growth retardation mitochondrial membrane, defective carnitine metabolism 300394 Cohen syndrome Mutation in COH1 gene: AR N Myeloid differentiation Retinopathy, developmental 216550 Pg unknown 607817 delay, facial dysmorphisms Clericuzio syndrome Mutation in C16ORF57 (USB1), AR N Myeloid differentiation Poikiloderma, MDS 604173 Poikiloderma with affects genomic integrity neutropenia 613276 JAGN1 deficiency Mutations in JAGN1, regulates AR N Myeloid differentiation Some with a bone phenotype 616022 secretory pathway 616012 3-Methylglutaconic Mutations in CLPB AR N Myeloid differentiation Microcephaly, hypoglycemia, Not yet assigned aciduria 616254 hypotonia, ataxia, seizures, cataracts, IUGR G-CSF receptor deficiency Mutations in CSF3R, the growth AR N Myeloid differentiation Poor response to GCSF 162830 factor receptor 138971 Disease Genetic defect/ Inheritance Affected cells Affected function Associated features OMIM number Presumed pathogenesis 2. Defects of Motility Leukocyte adhesion Mutation in ITGB2:Bchainfor AR N+M + Adherence, Delayed cord separation, 116920 deficiency adhesion proteins CD18/CD11 L+NK Chemotaxis, skin ulcers type 1 (LAD1) 600065 Endocytosis, Periodontitis Table 5 (continued) T/NK cytotoxicity Leukocyte adhesion Mutation in SLC35C1:GDP-Fucose AR N+M Rolling, Mild LAD type 1 features 266265 deficiency type 2 transporter chemotaxis plus hh-blood group plus (LAD2) 605881 mental and growth retardation Leukocyte adhesion Mutation in KINDLIN3: AR N+M + Adherence, chemotaxis LAD type 1 plus bleeding tendency 612840 deficiency type 3 Rap1-activation of β1-3 integrins L+NK (LAD3) 607901 Rac 2 deficiency Mutation in RAC2:Regulationof AD N Adherence, Poor wound healing, leukocytosis 608203 actin cytoskeleton chemotaxis − 602049 O2 production β-actin deficiency Mutation in ACTB:CytoplasmicActin AD N+M Motility Mental retardation, short stature 243310 102630 Localized juvenile Mutation in FPR1:Formylated AR N Formylpeptide induced Periodontitis only Not assigned periodontitis peptide receptor chemotaxis 136537 Papillon-Lefèvre Mutation in CTSC:CathepsinC AR N+M Chemotaxis Periodontitis, palmoplantar 245000 Syndrome activation of serine proteases hyperkeratosis in some patients 602365 Specific granule Mutation in C/EBPE:myeloid AR N Chemotaxis with bilobed nuclei 245480 deficiency transcription factor 189965 Shwachman-Diamond Mutation in SBDS: Defective AR N Chemotaxis Pancytopenia, exocrine pancreatic 260400 Syndrome ribosome synthesis607444 insufficiency, chondrodysplasia 3. Defects of − X-linked chronic Mutation in CYBB:Electron XL N+M Killing (faulty O2 production) McLeod phenotype in patients 306400 granulomatous disease transport protein (gp91phox) with deletions extending into (CGD) 300481 the contiguous Kell locus − Autosomal recessive CGD Mutation in CYBA:Electrontransport AR N+M Killing (faulty O2 production) Infections, autoinflammatory 233690 protein (p22phox) phenotype 608508 − Autosomal recessive CGD Mutation in NCF1:Adapter AR N+M Killing (faulty O2 production) Infections, autoinflammatory 233700 protein (p47phox) phenotype 608512 − Autosomal recessive CGD Mutation in NCF2:Activating AR N+M Killing (faulty O2 production) Infections, autoinflammatory 233710 protein (p67phox) phenotype 608515 − Autosomal recessive CGD Mutation in NCF4:Activating AR N+M Killing (faulty O2 production) Infections, autoinflammatory 613960 protein (p40 phox) phenotype 601488 4. Other Defects GATA2 deficiency Mutations in GATA2:loss AD +peripheral Multi lineage cytopenias Susceptibility to Mycobacteria, 614286 (Mono MAC syndrome) of stem cells DC; low NK cells papilloma viruses, histoplasmosis, 614172 137295 alveolar proteinosis, MDS/AML/CMML Pulmonary alveolar proteinosis* Mutation in CSF2RA Biallelic mutations in Alveolar GM-CSF signaling Alveolar proteinosis 300770 306250 pseudoautosomal gene

Total no. of genes in Table 5:31 New genes added: JAGN1, CLBP, CSF3R JClinImmunol lnImmunol Clin J Table 6 Defects in Intrinsic and Innate Immunity

Disease Genetic defect/Presumed Inheritance Affected Cell FunctionalDefect Associated Features Phenotype pathogenesis OMIM Number OMIM gene

1. Medelian Susceptibility to mycobacterial disease (MSMD) IL-12 and IL-23 Mutation in IL12RB1: AR L+NK IFN-γ secretion Susceptibility to Mycobacteria 614891 receptor β1chain IL-12 and IL-23 and Salmonella deficiency receptor β1chain 601604 IL-12p40 deficiency Mutation in IL12B : AR M IFN-γ secretion Susceptibility to Mycobacteria 614890 subunit p40 of and Salmonella IL12/IL23 161561 IFN-γ receptor 1 Mutation in IFNGR1: AR M+L IFN-γ binding Susceptibility to Mycobacteria 209950 deficiency IFN-γRligand and signaling and Salmonella binding chain 107470 IFN-γ receptor 1 Mutation in IFNGR1: AD M+L IFN-γ binding Susceptibility to Mycobacteria 615978 deficiency IFN-γRligand and signaling and Salmonella binding chain 107470 IFN-γ receptor 2 Mutation in IFNGR2: AR M+L IFN-γ signaling Susceptibility to Mycobacteria 614889 deficiency IFN-γRaccessory and Salmonella chain 147569 STAT1 deficiency Mutation in STAT1 AD M+L IFN-γsignaling Susceptibility to Mycobacteria, 614892 (AD form) (lost of function) Salmonella 600555 gp91 phox Mutation in CYBB: XL Mϕ only Killing (faulty Isolated susceptibility to mycobacteria 300645 − deficiency Electron transport O2 production) protein (gp 91 phox) 300481 IRF8-deficiency Mutation in IRF8: AD CD1c+MDC Differentiation of Susceptibility to Mycobacteria 614893 (AD form) IL12 production CD1c+MDC by CD1c+ MDC subgroup 601565 Tyk2deficiency Mutationin TYK2 AR Normal, but Normal Susceptibility to intracellular bacteria 611521 176941 Multiple cytokine (Mycobacteria, Salmonella), signaling defect fungi and viruses (+/−)ElevatedIgE ISG15 deficiency Mutation in ISG15 AR IFNγ defect production Susceptibility to Mycobacteria (BCG) 616126 147571 Brain calcification RORc deficiency Mutation in RORC AR L+NK lack of functional mycobacteriosis and candidiasis Not yet assigned 602943 RORγTprotein: IFNγ defect production complete absence of IL-17A/F-producing Tcells 2. Epidermodysplasia verruciformis EVER1 deficiency Mutations of TMC6 AR Keratinocytes and EVER proteins may HPV (group B1) infections and 226400 605828 leukocytes be involved in the cancer of the skin (typical EV) regulation of cellular zinc homeostasis in lymphocytes Table 6 (continued)

Disease Genetic defect/Presumed Inheritance Affected Cell FunctionalDefect Associated Features Phenotype pathogenesis OMIM Number OMIM gene

EVER2 deficiency Mutations of TMC8 AR Keratinocytes and EVER proteins may be HPV (group B1) infections and 226400 605829 leukocytes involved in the regulation cancer of the skin (typical EV) of cellular zinc homeostasis in lymphocytes WHIM (Warts, Hypogammaglo- Gain-of-function AD + Increased response of warts/Human Papilloma virus 193670 bulinemia, infections, Myelokathexis) mutations of Lymphocytes the CXCR4 chemokine (HPV) infection syndrome CXCR4,the receptor to its ligand Neutropenia receptor for CXCL12 (SDF-1) Reduced B cell number CXCL12 Hypogammaglobulinemia 162643 4. Predisposition to severe viral infection STAT1 deficiency Mutations of STAT1 AR TandNKcellsand STAT1-dependent Severe viral infections 613796 600555 monocytes IFN-α, and -β response Mycobacterial infection STAT2 deficiency Mutations of STAT2 AR TandNKcells STAT2-dependent Severe viral infections Not yet assigned 600556 IFN-α, and -β response (disseminated vaccine- strain measles) IRF7 deficiency Mutation in IRF7 AR Leukocytes and IFN-α, and -β production Severe influenza disease Not yet assigned 605047 plasmacytoid IFN-λ production dendritic cells, Non-hematopoietic cells CD16 deficiency Mutation in CD16 AR NK cells Deficient spontaneous Susceptibility to severe viral 615707 146740 NK cell cytotoxicity infections, inc. HSV, EBV, HPV 5. Herpes simplex encephalitis (HSE) TLR3 deficiency (b) Mutations AD Central nervous system TLR3-dependent Herpes simplex virus 1 encephalitis 613002 of TLR3 AR (CNS) resident IFN-α,-β,and-λ induction (incomplete clinical penetrance 603029 cells and fibroblasts for all etiologies listed here) UNC93B1 deficiency (a) Mutations of AR CNS resident cells UNC-93B-dependent Herpes simplex virus 1 encephalitis 610551 UNC93B1 and fibroblasts IFN-α,-β,and-λ induction 608204 TRAF3 deficiency (c) Mutations of AD CNS resident cells TRAF3-dependent Herpes simplex virus 1 encephalitis 614849 TRAF3 and fibroblasts IFN-α,-β,and-λ induction 601896 TRIF deficiency (c) Mutations of AD CNS resident cells TRIF-dependent Herpes simplex virus 1 encephalitis 614850 TRIF, also called AR and fibroblasts IFN-α,-β,and-λ induction TICAM1 607601 TBK1 deficiency (c) Mutations of TBK1 AD CNS resident cells TBK1-dependent Herpes simplex virus 1 encephalitis Not yet assigned 604834 and fibroblasts IFN-α,-β,and-λ induction 6. Predisposition to invasive fungal diseases CARD9 deficiency Mutations of CARD9 AR Mononuclear phagocytes CARD9 signaling pathway Invasive candidiasis infection 212050 607212 Deep dermatophytoses 7. Chronic mucocutaneous candidiasis (CMC)

IL-17RA deficiency (a) Mutations in IL17RA AR Epithelial cells, fibroblasts, IL-17RA signaling pathway CMC 613953 JClinImmunol 605461 mononuclear phagocytes Folliculitis IL-17RC deficiency Mutations in IL17RC AR Epithelial cells, fibroblasts, IL-17RC signaling pathway CMC Not yet assigned 610925 mononuclear phagocytes IL-17F deficiency (b) Mutations AD Tcells IL-17 F-containing dimers CMC 613956 in IL17F Folliculitis lnImmunol Clin J Table 6 (continued)

Disease Genetic defect/Presumed Inheritance Affected Cell FunctionalDefect Associated Features Phenotype pathogenesis OMIM Number OMIM gene

606496 STAT1 gain-of-function (c) gain-of-function AD T cells, B cells, monocytes Gain-of-function STAT1 CMC 614162 mutations in STAT1 mutations that impair the Various fungal, bacterial and 600555 development of IL-17- viral (HSV) infections producing T cells Auto-immunity (Thyroiditis, diabetes, cytopenia) Enteropathy ACT1 deficiency (c) Mutations in AR T cells, fibroblasts Fibroblasts fail to respond CMC 615527 ACT1, also called to IL-17A and IL-17 F, Blepharitis, Folliculitis and TRAF3IP2 and their T cells to IL-17E macroglossia (607043) 8. TLR signaling pathway deficiency IRAK-4 deficiency Mutations of IRAK4,a AR Lymphocytes + Granulocytes TIR-IRAK signaling pathway Bacterial infections (pyogens) 607676 component of TLR- +Monocytes and IL-1R-signaling pathway 606883 MyD88 deficiency Mutations of MYD88,a AR Lymphocytes + Granulocytes TIR-MyD88 signaling pathway Bacterial infections (pyogens) 612260 component of the +Monocytes TLR and IL-1R signaling pathway 602170 9. Isolated congenital Mutations in RPSA AD Spleen RPSA encodes ribosomal Bacteremia (encapsulated bacteria) 271400 asplenia (ICA) 150370 protein SA, a component No spleen of the small subunit of the ribosome 8. Trypanosomiasis Mutations in AD APOL-I Trypanosomiasis Not yet assigned APOL- I 603743

Total no. of gene defects in Table 6:32 New genes added : RORC, IRF7, IL17RC, APOL-1 XL X-linked inheritance, AR autosomal recessive inheritance, AD autosomal dominant inheritance, NF-κB nuclear factor Kappa B, TIR Toll and Interleukin 1 Receptor, IFN interferon, HVP human papilloma virus, TLR Toll-like receptor, IL interleukin Table 7 Autoinflammatory disorders

Disease Genetic defect/ Inheritance Affected cells Functional defects Associated Features Phenotype Presumed pathogenesis OMIM number OMIN gene

1. Defects effecting the inflammasome Familial Mediterranean Fever Mutations of MEFV AR Mature granulocytes, Decreased production of Recurrent fever, serositis 249100 (lead to gain of pyrin AD cytokine-activated pyrin permits ASC- and inflammation responsive 134610 function, resulting in monocytes. induced IL-1 processing to colchicine. Predisoposes inappropriate IL-1β release) and inflammation following to vasculitis and inflammatory 608107 subclinical serosal injury; bowel disease. macrophage apoptosis decreased. Mevalonate kinase deficiency Mutations of MVK (lead to AR affecting cholesterol synthesis; Periodic fever and leukocytosis 260920 (Hyper IgD syndrome) ablockinthemevalonate pathogenesis of disease unclear with high IgD levels pathway. Interleukin-1beta mediates the inflammatory phenotype) 251170 Muckle-Wells syndrome Mutations of NLRP3 AD PMNs Monocytes Defect in cryopyrin, involved Urticaria, SNHL, amyloidosis. 191900 (also called in leukocyte apoptosis and NALP3 CIAS1 or PYPAF1) NFkB signaling and IL-1 (lead to constitutive activation processing of the NLRP3 inflammasome) 606416 Familial cold autoinflammatory Mutations of NLRP3 AD PMNs, monocytes same as above Non-pruritic urticaria, arthritis, 120100 syndrome 1 (See above) chills, fever and leukocytosis 606416 after cold exposure. Familial cold Mutations of NLRP12 AD PMNs, monocytes same as above Non-pruritic urticaria, arthritis, 611762 autoinflammatory syndrome 2 609648 chills, fever and leukocytosis after cold exposure. Neonatal onset multisystem Mutations of NLRP3 AD PMNs, chondrocytes same as above Neonatal onset rash, chronic 607115 inflammatory disease CIAS1 (See above) meningitis, and arthropathy (NOMID) or chronic infantile 606416 with fever and inflammation. neurologic cutaneous and articular syndrome (CINCA) NLRC4-MAS (macrophage Mutation in NLRC4 AD PMNs monocytes Gain of function mutation Severe enterocolitis and 616050 activating syndrome) (see functional defect) macrophages in NLRC4 results in macrophage 616115 Familial cold 606831 elevated secretion of activation syndrome autoinflammatory syndrome 4 IL-1β and IL-18 as well as macrophage activation PLAID (PLCγ2associated Mutation in PLCG2 AD Bcells,NK,Mastcells Mutationscauseactivation Cold urticaria 614468 antibody deficiency and ((see functional defect) of IL-1 pathways hypogammaglobulinemia immune dysregulation) 600220 Familial cold autoinflammatory syndrome 3 APLAID (autoinflammation Mutation (c2120C>A) AD Bcells,NK,mastcells Themutationleadstoactivation Blistering skin lesion, 614878 and PLCγ2associatedantibody in PLCG2 (see function defect) of the NLRP3 inflammasome pulmonary and deficiency and immune dysregulation) 600220 (not provoked by cold temperature) bowel disease 2. Non inflammasome-related conditions (TNF receptor-associated Mutations of TNFRSF1A AD PMNs, monocytes Mutations of 55-kD TNF receptor Recurrent fever, serositis, 142680 periodic syndrome (TRAPS) (resulting in increased leading to intracellular receptor rash, and ocular or joint JClinImmunol TNF inflammatory signaling) retention or diminished soluble inflammation 191190 cytokine receptor available to bind TNF Pyogenic sterile arthritis, Mutations of PSTPIP1 AD Hematopoietic tissues, Disordered actin reorganization Destructive arthritis, inflammatory 604416 pyoderma gangrenosum, (also called C2BP1) upregulated in leading to compromised skin rash, myositis acne (PAPA) syndrome (affects both pyrin and activated T-cells lnImmunol Clin J Table 7 (continued)

Disease Genetic defect/ Inheritance Affected cells Functional defects Associated Features Phenotype Presumed pathogenesis OMIM number OMIN gene

protein tyrosine phosphatase physiologic signaling during to regulate innate and inflammatory response adaptive immune responses) 606347 Blau syndrome Mutations of NOD2 (also AD Monocytes Mutations in nucleotide binding Uveitis, granulomatous synovitis, 186580 called CARD15) (involved site of CARD15, possibly camptodactyly, rash and cranial in various inflammatory processes) disrupting interactions with neuropathies, 30 % develop 605956 lipopolysaccharides and NF-κB Crohn’sdisease signaling ADAM17 deletion Mutation in ADAM17 (leads to AR Leukocytes and Defective TNFα production Early onset diarrhea and 614328 tumor necrosis factor α epithelial cells skin lesions converting enzyme deficiency) 603639 Chronic recurrent multifocal Mutations of LPIN2 (increased AR Neutrophils, bone undefined Chronic recurrent multifocal 609628 osteomyelitis and congenital expression of the marrow cells osteomyelitis, transfusion- dyserythropoietic anemia proinflammatory genes) dependent anemia, cutaneous (Majeed syndrome) 605519 inflammatory disorders DIRA (Deficiency of the Mutations of IL1RN AR PMNs, Monocytes Mutations in the IL1 receptor Neonatal onset of sterile 612852 Interleukin 1 Receptor (see functional defect) antagonist allow unopposed multifocal osteomyelitis, Antagonist) 147679 action of Interleukin 1 periostitis and pustulosis. DITRA – Deficiency Mutation in IL36RN AR Keratinocyte Leukocytes Mutations in IL-36RN leads Pustular Psoriasis 614204 of IL-36 receptor antagonist (see functional defect) to increase IL-8 production 605507 SLC29A3 mutation Mutation in SLC29A3 AR Leukocyte, bone cells Hyperpigmentation hypertrichosis Histiocytosis-lymphadenopathy 602782 612373 plus syndrome CAMPS (CARD14 Mutation in CARD14 AD Mainly in Keratinocyte Mutations in CARD14 activate Psoriasis 602723 mediated psoriasis) (see functional defect) the NF-kBpathwayand 607211 production of IL-8 Cherubism Mutation in SH3BP2 AD Stroma cells, bone cells Hyperactived macrophage Bone degeneration in jaws 118400 (see functional defect) and increase NF-kB 602104 CANDLE (chronic atypical Mutation in PSMB8, AR Keratinocyte, B cell Mutations cause increase Dystrophy, panniculitis 256040 neutrophilic dermatitis (see functional defect) adipose cells IL-6 production with lipodystrophy) 177046 COPA defect Mutation in COPA AD PMNs and tissues Mutant COPA leads to Autoimmune inflammatory 601924 (Coatamer protein specific cells defective intracellular arthritis and interstitial lung complex, subunit alpha) transport via the coat protein disease with Th17 dysregulation complex I (COPI) and autoantibody production

Total no. of gene defects in Table 7:17 New genes added: NLRC4, ADAM17, COPA Notes: Autoinflammatory diseases are clinical disorders marked by abnormally increased inflammation, mediated predominantly by the cells and molecules of the innate immune system, with a significant host predisposition. While the genetic defect of one of the most common autoinflammatory conditions, PFAPA, is not known, recent studies suggest thatitisassociatedwithactivationofIL-1pathwayand response to IL-1beta antagonists Muckle-Wells syndrome, familial cold autoinflammatory syndrome and neonatal onset multisystem inflammatory disease (NOMID) which is also called chronic infantile neurologiccutaneousandarticular syndrome (CINCA) are caused by similar mutations in CIAS1/NLRP3 mutations. The disease phenotype in any individual appears to dependonmodifyingeffectsofothergenesandenvironmentalfactors AR autosomal recessive inheritance, AD autosomal dominant inheritance, PMN polymorphonuclear cells, ASC apoptosis-associated speck-like protein with a caspase recruitment domain, CARD caspase recruitment domain, CD2BP1 CD2 binding protein-1, PSTPIP1 Proline/serine/threonine phosphatase-interacting protein 1, SNHL sensorineural hearing loss, CIAS1 cold-induced autoinflammatory syndrome 1 Table 8 Complement deficiencies

Disease Genetic defect; presumed pathogenesis Inheritance Laboratory features Associated Features Phenotype OMIM gene OMIM number

1) Integral complement cascade component deficiencies C1q deficiency C1QA,:Classicalcomplement AR Absent CH50 hemolytic activity, SLE, infections with 613652 pathway component Defective activation of the encapsulated organisms 120550 classical pathway Diminished clearance of apoptotic cells C1q deficiency C1QB: Classical complement AR Absent CH50 hemolytic activity, SLE, infections with 613652 pathway component Defective activation of the encapsulated organisms 120570 classical pathway Diminished clearance of apoptotic cells C1q deficiency C1QC: Classical complement AR Absent CH50 hemolytic activity, SLE, infections with 613652 pathway component Defective activation of the classical pathway encapsulated organisms 120575 Diminished clearance of apoptotic cells C1r deficiency C1R:Classicalcomplement AR Absent CH50 hemolytic activity, Defective SLE, infections with 216950 pathway component activation of the classical pathway encapsulated organisms 613785 C1s deficiency C1S:Classicalcomplement AR Absent CH50 hemolytic activity SLE, infections with 613783 pathway component Defective activation of the classical pathway encapsulated organisms 120580 C4 deficiency C4A, Classical complement AR Absent CH50 hemolytic activity, SLE, infections with 614380 pathway components Defective activation of the classical pathway encapsulated organisms 120810 Complete deficiency requires biallelic mutations/deletions/conversions of both C4A and C4B C4 deficiency C4B:Classicalcomplement AR Absent CH50 hemolytic activity, Defective SLE, infections with 614379 pathway components activation of the classical pathway encapsulated organisms 120820 Complete deficiency requires biallelic mutations/deletions/conversions of both C4A and C4B C2 deficiency C2:Classicalcomplement AR Absent CH50 hemolytic activity, SLE, infections with encapsulated 613927 pathway component Defective activation of the classical pathway organisms, atherosclerosis 217000 C3 deficiency C3:Centralcomplementcomponent AR Absent CH50 and AH50 hemolytic activity Infections; glomerulonephritis; 613779 LOF 120700 Defective opsonization Atypical Hemolytic-uremic Defective humoral immune response syndrome with gain-of-function mutations. C3 GOF C3:Centralcomplementcomponent Gain-of-function AD Increased activation of complement Atypical Hemolytic-uremic 612925 120700 syndrome C5 deficiency C5:Terminalcomplementcomponent AR Absent CH50 and AH50 hemolytic activity Neisserial infections 609536 120900 Defective bactericidal activity C6 deficiency C6:Terminalcomplementcomponent AR Absent CH50 and AH50 hemolytic activity Neisserial infections 612446 217050 Defective bactericidal activity C7 deficiency C7:Terminalcomplementcomponent AR Absent CH50 and AH50 hemolytic activity Neisserial infections 610102 217070 Defective bactericidal activity C8 αdeficiency C8A:Terminalcomplementcomponent AR Absent CH50 and AH50 hemolytic activity Neisserial infections 613790

120950 Defective bactericidal activity JClinImmunol C8γ deficiency C8G: Terminal complement component AR Absent CH50 and AH50 hemolytic activity Neisserial infections 613790 120930 Defective bactericidal activity C8β deficiency C8B:Terminalcomplementcomponent AR Absent CH50 and AH50 hemolytic activity Neisserial infections 613789 120960 Defective bactericidal activity C9 deficiency C9:Terminalcomplementcomponent AR Reduced CH50 and AP50 hemolytic activity Mild susceptibility to 613825 120940 Deficient bactericidal activity Neisserial infections lnImmunol Clin J Table 8 (continued)

Disease Genetic defect; presumed pathogenesis Inheritance Laboratory features Associated Features Phenotype OMIM gene OMIM number

MASP2 deficiency MASP2:CleavageofC4 AR Deficient activation of the lectin Pyogenic infections; 613791 605102 activation pathway Inflammatory lung disease, autoimmunity Ficolin 3 deficiency FCN3: Activates the classical AR Absence of complement activation Respiratory infections, 613860 complement pathway by the Ficolin 3 pathway. abscesses 604973 2) Complement Regulatory defects C1 inhibitor deficiency SERPING1:regulationofkinins AD Spontaneous activation of the complement Hereditary angioedema 106100 and complement activation pathway with consumption of C4/C2 606860 Spontaneous activation of the contact system with generation of bradykinin from high molecular weight kininogen Factor B CFB: Activation of the alternative AD Gain-of-function mutation with increased aHUS 612924 pathway spontaneous AH50 138470 Factor D deficiency CFD:Regulationofthealternative AR Absent AH50 hemolytic activity Neisserial infections 613912 complement pathway 134350 Properdin deficiency CFP:Regulationofthealternative XL Absent AH50 hemolytic activity Neisserial infections 312060 complement pathway 300383 Factor I deficiency CFI:Regulationofthe alternative AR Spontaneous activation of the alternative Infections, Neisserial 610984 complement pathway complement pathway with infections, aHUS, 612923 217030 consumption of C3 preeclampsia Factor H deficiency CFH:Regulationofthealternative AR/AD Spontaneous activation of the alternative Infections, Neisserial infections, 609814 complement pathway complement pathway with consumption of C3 aHUS, preeclampsia 235400 134370 Factor H –related CFHR1-5:BindC3b AR/AD Normal CH50, AH50, autoantibodies to aHUS, Neisserial infections 235400 protein deficiencies 134371 Factor H. Linked deletions of one or 600889 more CFHR genes leads to susceptibility 605336 autoantibody-mediated aHUS 605337 608593 Thrombomodulin THBD:Regulatescomplement AD Normal CH50, AH50 aHUS 612926 and coagulant activation 188040 Complement Receptor 3 ITGAM AR CR3 expression is lost in LAD1. Infections 609939 (CR3) deficiency 120980 See LAD1 in Table 5 Membrane Cofactor Protein CD46:Dissociates AD Inhibitor of complement alternate aHUS, infections, 612922 (CD46) deficiency C3b and C4b pathway, decreased C3b binding preeclampsia 120920 Membrane Attack Complex CD59: Regulates the AR Erythrocytes highly susceptible to Hemolytic anemia, 612300 Inhibitor (CD59) deficiency membrane attack complement-mediated lysis polyneuropathy complex formation 107271

Total no. of genes Tables 8 and 9:30 No new genes added to the 2015 classification XL X-linked inheritance, AR autosomal recessive inheritance, AD autosomal dominant inheritance, MAC membrane attack complex, SLE systemic lupus erythematosus, MASP MBP associated serine protease 2 Table 9 Phenocopies of PID

Disease Genetic defect/presumed pathogenesis Circulating T cells Circulating B cells Serum Ig Associated features/similar PID

Associated with somatic mutations Autoimmune lymphoproliferative Somatic mutation in TNFRSF6 Increased CD4−CD8−double Normal, but increased Normal or Splenomegaly, lymphadenopathy, syndrome (ALPS–SFAS) negative (DN) T alpha/beta number of CD5+ B increased autoimmune cytopenias cells cells Defective lymphocyte apoptosis/ ALPS–FAS (=ALPS type Im) RAS-associated autoimmune Somatic mutation in KRAS Normal Bcelllymphocytosis Normalor Splenomegaly, lymphadenopathy, leukoproliferative (gain-of-function) increased autoimmune cytopenias, disease (RALD) granulocytosis, / ALPS-like RAS-associated autoimmune Somatic mutation in NRAS (gain-of- Increased CD4−CD8−double Lymphocytosis Splenomegaly, lymphadenopathy, leukoproliferative disease function) negative (DN) T alpha/beta autoantibodies/ALPS-like (RALD) cells Cryopyrinopathy, (Muckle- Somatic mutation in NLRP3 Normal Normal Normal Urticaria-likerash,arthropathy, Wells /CINCA/NOMID- neurological symptoms like syndrome) Associated with autoantibodies Chronic mucocutaneous Germline mutation in Normal Normal Normal Endocrinopathy, chronic candidiasis AIRE AutoAb to IL-17 mucocutaneous (isolated or with APECED and/or IL-22 candidiasis/CMC syndrome) Adult-onset immunodeficiency AutoAb to IFN gamma Decreased naive T cells Normal Normal Mycobacterial, fungal, Salmonella VZV infections/MSMD, or CID Recurrent skin infection AutoAb to IL-6 Normal Normal Normal Staphylococcal infections/STAT3 deficiency Pulmonary alveolar proteinosis AutoAb to GM-CSF Normal Normal Normal Pulmonary alveolar proteinosis, cryptococcal meningitis/CSF2RA deficiency Acquired angioedema AutoAb to CI inhibitor Normal Normal Normal Angioedema/C1 INH deficiency (hereditary angioedema) Atypical Hemolytic AutoAb to Complement Factor H Normal Normal Normal aHUS Uremic Syndrome Spontaneous activation of the alternative complement pathway JClinImmunol J Clin Immunol

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