Journal of Clinical Immunology

, Volume 35, Issue 8, pp 696–726

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

  • Capucine Picard
  • Waleed Al-Herz
  • Aziz Bousfiha
  • Jean-Laurent Casanova
  • Talal Chatila
  • Mary Ellen Conley
  • Charlotte Cunningham-Rundles
  • Amos Etzioni
  • Steven M. Holland
  • Christoph Klein
  • Shigeaki Nonoyama
  • Hans D. Ochs
  • Eric Oksenhendler
  • Jennifer M. Puck
  • Kathleen E. Sullivan
  • Mimi L K. Tang
  • Jose Luis Franco
  • H. Bobby Gaspar
Open AccessOriginal Research

DOI: 10.1007/s10875-015-0201-1

Cite this article as:
Picard, C., Al-Herz, W., Bousfiha, A. et al. J Clin Immunol (2015) 35: 696. doi:10.1007/s10875-015-0201-1

Abstract

We report the updated classification of primary immunodeficiencies compiled by the Primary Immunodeficiency Expert Committee (PID EC) of the International Union of Immunological Societies (IUIS). In the two years since the previous version, 34 new gene defects are reported in this updated version. For each disorder, the key clinical and laboratory features are provided. In this new version we continue to see the increasing overlap between immunodeficiency, as manifested by infection and/or malignancy, and immune dysregulation, as manifested by auto-inflammation, auto-immunity, and/or allergy. There is also an increased number of genetic defects that lead to susceptibility to specific organisms which reflects the finely tuned nature of immune defense systems. This classification is the most up to date catalogue of all known and published primary immunodeficiencies and acts as a current reference of the knowledge of these conditions and is an important aid for the genetic and molecular diagnosis of patients with these rare diseases.

Keywords

Primary immunodeficiencies classification genetic defects 

Background

The International Union of Immunological Societies (IUIS) Expert Committee on Primary Immunodeficiency met in London on the 14th and 15th March 2015 to update the classification of human primary immunodeficiencies (PIDs). This report represents the most current and complete catalogue of known PIDs. It serves as a reference for these conditions and provides a framework to help in the diagnostic approach to patients suspected to have PID.

As in previous reports, we have classified the conditions into major groups of PIDs and these are now represented in 9 different tables (Tables 1, 2, 3, 4, 5, 6, 7,8 and 9). In each table, we list the condition, its genetic defect if known and the major immunological and in some conditions the non-immunological abnormalities associated with the disease. This year we have added the gene OMIM number as well as the phenotype OMIM number for ease of reference.
Table 1

Immunodeficiencies affecting cellular and humoral immunity

Disease

Genetic defect/Presumed pathogenesis

Gene OMIM

Inheritance

Circulating T cells

Circulating B cells

Serum Ig

Associated Features

Phenotype

OMIM number

TB+ Severe Combined Immunodeficiency (SCID)

 γc deficiency

Mutation of IL2RG

Defect in γ chain of receptors for IL-2, -4, -7, -9, -15, -21

308380

XL

Markedly decreased

Normal or increased

Decreased

Markedly decreased NK cells;

300400

 JAK3 deficiency

Mutation of JAK3

Defect in Janus activating kinase 3

600173

AR

Markedly decreased

Normal or increased

Decreased

Markedly decreased NK cells;

600802

 IL7Rα deficiency

Mutation of IL7RA

Defect in IL-7 receptor α chain

146661

AR

Markedly decreased

Normal or increased

Decreased

Normal NK cells

608971

 CD45 deficiency

Mutation of PTPRC

Defect in CD45

151460

AR

Markedly decreased

Normal

Decreased

Normal γ/δ T cells

608971

 CD3δ deficiency

Mutation of CD3D

Defect in CD3δ, chain of T cell antigen receptor complex

186790,

AR

Markedly decreased

Normal

Decreased

Normal NK cells

No γ/δ T cells

615617

 CD3ε deficiency

Mutation of CD3E

Defect in CD3ε chain of T cell antigen receptor complex

186830,

AR

Markedly decreased

Normal

Decreased

Normal NK cells

No γ/δ T cells

615615

 CD3ζ deficiency

Mutation of CD3Z

Defect in CD3ζ chain of T cell antigen receptor complex

186780

AR

Markedly decreased

Normal

Decreased

Normal NK cells

No γ/δ T cells

610163

 Coronin-1A deficiency

Mutation of CORO1A Defective thymic egress of T cells and defective T cell locomotion

605000

AR

Markedly decreased

Normal

Decreased

Detectable thymus

EBV-associated B-cell lymphoproliferation

615401

TB SCID

 DNA recombination defects (for additional DNA repair defects see Table 2)

 RAG 1 deficiency

Mutation of RAG1

Defective VDJ recombination; defect of recombinase activating gene (RAG) 1

179615

AR

Markedly decreased

Markedly decreased

Decreased

 

601457

 RAG 2 deficiency

Mutation of RAG2

Defective VDJ recombination; defect of recombinase activating gene (RAG) 2

179616

AR

Markedly decreased

Markedly decreased

Decreased

 

601457

 DCLRE1C (Artemis) deficiency

Mutation of ARTEMIS

Defective VDJ recombination; defect in Artemis DNA recombinase-repair protein

605988

AR

Markedly decreased

Markedly decreased

Decreased

Radiation sensitivity

602450

 DNA PKcs deficiency

Mutation of PRKDC Defective VDJ recombination; defect in DNA PKcs

Recombinase repair protein

600899

AR

Markedly decreased

Markedly decreased

variable

Radiation sensitivity, microcephaly and developmental defects

Autoimmunity and granuloma

615966

  Cernunnos/XLF deficiency

Mutation of Cernunnos Defective VDJ recombination; defect in Cernunnos

611290

AR

Markedly decreased

Markedly decreased

Decreased

Radiation sensitivity, microcephaly and developmental defects

611291

 DNA ligase IV deficiency

Mutation of LIG4 Defective VDJ recombination; defect in DNA ligase IV

601837

AR

Markedly decreased

Markedly decreased

Decreased

Radiation sensitivity, microcephaly and developmental defects

606593

 Reticular dysgenesis, AK2 deficiency

Mutation of AK2

Defective maturation of lymphoid and myeloid cells (stem cell defect)

Defect in mitochondrial adenylate kinase 2.

103020

AR

Markedly decreased

Decreased or normal

Decreased

Granulocytopenia and deafness

267500

 Adenosine deaminase (ADA) deficiency

Mutation of ADA

Absent ADA activity, elevated lymphotoxic metabolites (dATP, S-adenosyl homocysteine)

608958

AR

Absent from birth (null mutations) or progressive decrease

Absent from birth of progressive decrease

Progressive decrease

Decreased NK cells, often with costochondral junction flaring, neurological features, hearing impairment, lung and liver manifestations; partial ADA deficiency may lead to delayed or milder presentation

102700

 Combined immunodeficiencies generally less profound than severe combined immunodeficiency

 DOCK2 deficiency

Mutations in DOCK2 required for RAC1 activation, actin polymerization, T-cell proliferation, chemokine-induced lymphocyte migration and NK-cell degranulation

603122

AR

Decreased. Poor response to PHA. Low TRECs

Normal

Decreased/ Normal. Poor antibody responses

Normal NK numbers, but defective function. Impaired interferon responses in hematopoietic and non-hematopoietic cells

616433

 CD40 ligand deficiency

Mutation of CD40LG Defects in CD40 ligand (CD40L; also called TNFSF5 or CD154) cause defective isotype switching and impaired dendritic cell signaling

300386

XL

Normal; may progressively decrease

sIgM+ and sIgD+ B cells present, other surface isotype positive B cells absent

IgM increased or normal, other isotypes decreased

Neutropenia, thrombocytopenia; hemolytic anemia, biliary tract and liver disease, opportunistic infections

308230

 CD40 deficiency

Mutation of CD40 (also called TNFRSF5)

Defects in CD40 cause defective isotype switching and impaired dendritic cell signaling

109535

AR

Normal

IgM+ and IgD+ B cells present, other isotypes absent

IgM increased or normal, other isotypes decreased

Neutropenia, gastrointestinal and liver/biliary tract disease, opportunistic infections

606843

 ICOS deficiency

Mutations in ICOS; a co-stimulatory molecule expressed on T cells

604558

AR

Normal

Normal

Low

Recurrent infections; autoimmunity, gastroenteritis, may have granulomas

607594

 CD3γ deficiency

Mutation of CD3G. Defect in CD3γ component of the T cell antigen receptor complex

186740

AR

Normal, but reduced TCR expression

Normal

Normal

 

615607

 CD8 deficiency

Mutation of CD8A. Defects of CD8 α chain, important for maturation and function of CD8 T cells

186910

AR

Absent CD8, normal CD4 cells

Normal

Normal

  

 ZAP-70 deficiency

Mutation in ZAP70 intracellular signaling kinase, acts downstream of TCR

176947

AR

Decreased CD8, normal CD4 cells

Normal

Normal

Autoimmunity in some cases

269840

 MHC class I deficiency

Mutations in TAP1, gene, causing MHC class I non-expression

170260

AR

Decreased CD8, normal CD4 cells;

absent MHC I expression on lymphocytes

Normal

Normal

Vasculitis; pyoderma gangrenosum

604571

 MHC class I deficiency

Mutations in TAP2, gene, causing MHC class I non-expression

170261

AR

Decreased CD8, normal CD4 cells;

absent MHC I expression on lymphocytes

Normal

Normal

Vasculitis; pyoderma gangrenosum

604571

 MHC class I deficiency

Mutations in TAPBP (tapasin) gene, causing MHC class I non-expression

601962

AR

Decreased CD8, normal CD4 cells;

absent MHC I expression on lymphocytes

Normal

Normal

Vasculitis; pyoderma gangrenosum

604571

 MHC class I deficiency

Mutations in B2M gene, causing MHC class I non-expression

109700

AR

Decreased CD8, normal CD4 cells;

absent MHC I expression on lymphocytes

Normal

Normal

Sinopulmonary infections, cutaneous granuloma, hypoproteinemia. Absent expression of β2m associated proteins like MHC-I, CD1a, and CD1b, CD1c on β2m-deficient cells

not yet assigned

 MHC class II deficiency group A

Mutation in transcription factors for MHC class II proteins (CIITA gene)

600005

AR

Decreased CD4 cells

Absent MHC II expression on lymphocytes

Normal

Normal or decreased

Failure to thrive, diarrhea, respiratory tract infections liver/biliary tract disease

209920

 MHC class II deficiency

group B

Mutation in transcription factors for MHC class II proteins RFXANK gene

603200

AR

Decreased CD4 cells

Absent MHC II expression on lymphocytes

Normal

Normal or decreased

Failure to thrive, diarrhea, respiratory tract infections liver/biliary tract disease

209920

 MHC class II deficiency group C

Mutation in transcription factors for MHC class II proteins RFX5, gene)

601863

AR

Decreased CD4 cells

Absent MHC II expression on lymphocytes

Normal

Normal or decreased

Failure to thrive, diarrhea, respiratory tract infections liver/biliary tract disease

209920

 MHC class II deficiency

group D

Mutation in transcription factors for MHC class II proteins (RFXAP gene

601861

AR

Decreased CD4 cells

Absent MHC II expression on lymphocytes

Normal

Normal or decreased

Failure to thrive, diarrhea, respiratory tract infections liver/biliary tract disease

209920

 ITK deficiency

Mutations in ITK encoding IL-2 inducible T cell kinase required for TCR-mediated activation

186973

AR

Progressive decrease

Normal

Normal or decreased

EBV associated B cell lymphop-roliferation, lymphoma

Normal or decreased IgG

613011

 MAGT1 deficiency

Mutations in MAGT1, Impaired Mg++ flux leading to impaired TCR signaling 300715

XL

Decreased CD4 cells reduced numbers of RTE, impaired T-cell proliferation in response to CD3

Normal

Normal

EBV infection, lymphoma; viral infections, respiratory and GI infections,

300853

 DOCK8 deficiency

Mutations in DOCK8 encoding a dedicator of cytokinesis regulator of intracellular actin reorganisation

611432

AR

Decreased; Impaired T lymphocyte proliferation; Treg deficiency and poor function

Decreased; low CD27+ memory B cells

Low IgM, increased IgE

Decreased NK cells with impaired function, hypereosinophilia, recurrent infections; severe atopy, extensive cutaneous viral and staphylococcal infections, susceptibility to cancer. Defects in peripheral B tolerance.

243700

 RhoH deficiency

Mutations in RHOH – an atypical Rho GTPase transducing signals downstream of various membrane receptors

602037

AR

Normal

low naïve T cells and RTE, restricted T cell repertoire and impaired T cells proliferation in response to CD3 stimulation.

Normal

Normal

HPV infection, lymphoma, lung granulomas, molluscum contagiosum,

not yet assigned

 MST1 deficiency

Mutations in STK4 – a serine/threonine kinase

604965

AR

Decreased increased proportion of terminal differentiated effector memory cells (TEMRA), low naïve T cells, restricted T cell repertoire in the TEMRA population and impaired T cells proliferation

Decreased

High

Recurrent bacterial, viral, and candidal infections; intermittent neutropenia; EBV-driven lymphoproliferation; lymphoma; Congenital heart disease, autoimmune cytopenias; HPV infection.

614868

  TCRα deficiency

Mutations in TRAC – essential component of the T cell receptor

186880

AR

Normal All CD3 T cells expressed TCRγδ (or may be better to say: TCRαβ T-cell deficiency), impaired T cells proliferation

Normal

Normal

Recurrent viral, bacterial and fungal infections, immune dysregulation autoimmunity, and diarrhea.

615387

 LCK deficiency

Defects in LCK – a proximal tyrosine kinase that interacts with TCR

153390

AR

Normal total numbers but CD4+ T-cell lymphopenia, low Treg numbers, restricted T cell repertoire and impaired TCR signaling

Normal

Normal IgG and IgA and increased IgM

Diarrhea, recurrent infections, immune dysregulation autoimmunity,

615758

 MALT1 deficiency

Mutations in MALT1

a caspase-like cysteine protease that is essential for nuclear factor-kappa-B activation

604860

AR

Normal number but impaired T cells proliferation

Normal

Normal

Impaired antibody response

Bacterial, fungal and viral infections

615468

 CARD11 deficiency

Defects in CARD11 – acts as a scaffold for NF-КB activity in the adaptive immune response

607210

AR

Normal predominance of naive T-lymphocyte, impaired T cells proliferation

Normal predominance of transitional B lymphocytes,

Absent/low

Pneumocystis jirovicii pneumonia, bacterial infections,

615206

 BCL10 deficiency

Mutations in BCL10 which encodes the B cell CLL / lymphoma 10 protein that forms a heterotrimer with Malt1 and CARD family adaptors and plays a role in NF-kB signaling

603517

AR

Normal numbers, low memory T and Tregs, decreased proliferation to antigen and anti-CD3

Normal number; decreased memory and switched B cells

Low

Recurrent bacterial and viral infections, candidiasis, gastroenteritis

616098

 IL-21 deficiency

Mutation in IL21

605384

AR

Normal number.

Normal/low function

Low

IgG deficiency

Severe early onset colitis

615767

 IL-21R deficiency

Defects in IL21R – together with common gamma chain binds IL-21

605383

AR

Abnormal T cell cytokine production; Abnormal T cell proliferation to specific stimuli

Normal

Normal but impaired specific responses

Suspectibility to cryptoporidia and pneumocystis and cholangitis

615207

 OX40 deficiency

Defects in OX40 (TNFRSF4) encoding a co-stimulatory molecule expressed on activated T cells

600315

AR

Normal T cell numbers; decreased antigen specific memory CD4+ cells

Normal B cell numbers; reduced frequency of memory B cells

Normal

Kaposi’s sarcoma; impaired immunity to HHV8

615593

 IKBKB deficiency

Defects in IKBKB, encoding IkB 2 kinase 2, a component of the NF-kB pathway

603258

AR

Normal total T cells; absent regulatory and γδ T cells; impaired TCR activation

Normal B cell numbers; impaired BCR activation;

Decreased

Recurrent bacterial, viral and fungal infections; clinical phenotype of SCID

615592

 LRBA deficiency

Mutations in LRBA (lipopolysaccharide responsive beige-like anchor protein)

606453

AR

Normal or decreased CD4 numbers; T cell dysregulation

Low or normal numbers of B cells

Reduced I IgG and IgA in most

Recurrent infections, inflammatory bowel disease, autoimmunity; EBV infections

614700

 CD27 deficiency

Mutations in CD27 (TNFRSF7) encoding TNF-R member superfamily required for generation and long-term maintenance of T cell immunity

186711

AR

Normal

No memory B cells

Hypogamma-globulinaemia following EBV infection

Clinical and immunologic features triggered by EBV infection, HLH

Aplastic anaemia, Lymphoma,

hypogammaglobulinemia,

Low iNKT cells

615122

 NIK deficiency

Mutation in MAP3K14, encoding NIK (NF-kB-inducing kinase)

604655

AR

Normal number; impaired proliferation in response to antigen stimulation. Polycloncal Vβ repertoires

Decreased total peripheral B cell and switched memory B cells

Hypogamma-globulinaemia

Recurrent bacterial, viral and Cryptosporidium infections. Low NK cell number and defective NK cell activation

Not yet assigned

 CTPS1 deficiency

Mutation in CTPS1, encoding CTP synthase 1, essential for lymphocyte proliferation

123860

AR

Normal or decreased number

Normal or decreased proliferation

Normal/low number

Normal/high IgG

Recurrent/chronic viral infections specially EBV and VZV, bacterial infections, EBV-driven

B-cell non-Hodgkin lymphoma

615897

 Omenn syndrome

Hypomorphic mutations in RAG1, RAG2, Artemis, IL7RA, RMRP, ADA, DNA Ligase IV, IL2RG, AK2, or associated with DiGeorge syndrome; some cases have no defined gene mutation

 

Present; restricted T cell repertoire and impaired function

Normal or decreased

Decreased, except for increased IgE

Erythroderma, eosinophilia, adenopathies, hepatosplenomegaly

603554

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. Both OS and leaky SCID can be associated with >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 leukocyte motility and is reported in Table 5; however, one patient with RAC2 deficiency had absent T cell receptor excision circles (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, it should be noted that individuals with the 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. 2012 Feb 9;119(6):1399–406. doi: 10.1182/blood-2011-04-350686. Epub 2011 Dec 19). See Erratum (Blood. 2014 Jan 16;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

Table 2

Combined immunodeficiencies with associated or syndromic features

Disease

Genetic defect/Presumed pathogenesis

OMIM number gene locus

Inheritance

Circulating T cells

Circulating B cells

Serum Ig

Associated features

OMIM number

Phenotype

1. Congenital thrombocytopenia

 Wiskott-Aldrich syndrome (WAS)

Mutations in WAS; cytoskeletal and immunologic synapse defect affecting haematopoietic stem cell derivatives

301000

XL

Progressive decrease, Abnormal lymphocyte responses to anti-CD3

Normal numbers

Decreased IgM: antibody to polysaccharides particularly decreased; often increased IgA and IgE

Thrombocytopenia with small platelets; eczema; lymphoma; autoimmune disease; IgA nephropathy; bacterial and viral infections. XL thrombocytopenia is a mild form of WAS, and XL neutropenia is caused by missense mutations in the GTPase binding domain of WASP

300392

 WIP deficiency

Mutations in WIPF1; cytoskeletal and immunologic synapse defect affecting haematopoietic stem cell derivatives 602357

AR

Reduced, Defective lymphocyte responses to anti-CD3

Low

Normal, except for increased IgE

Recurrent infections; eczema; thrombocytopenia. WAS-like phenotype.

614493

2. DNA repair defects (other than those in Table 1)

 Ataxia-telangiectasia

Mutations in ATM; disorder of cell cycle check-point and DNA double- strand break repair

607585

AR

Progressive decrease, abnormal proliferation to mitogens

Normal

Often decreased IgA, IgE and IgG subclasses; increased IgM monomers; antibodies variably decreased

Ataxia; telangiectasia; pulmonary infections; lymphoreticular and other malignancies; increased alpha fetoprotein and increased radiosensitivity; chromosomal instability

208900

 Nijmegen breakage syndrome

Hypomorphic mutations in NBS1

(Nibrin); disorder of cell cycle checkpoint and DNA double- strand break repair

602667

AR

Progressive decrease

Variably reduced

Often decreased IgA, IgE and IgG subclasses; increased IgM; antibodies variably decreased

Microcephaly; bird-like face; lymphomas; solid tumors; increased radiosensitivity; chromosomal instability

251260

 Bloom syndrome

Mutations in BLM (RECQL3); encoding DNA helicase RecQ protein-like 3 helicase

604610

AR

Normal

Normal

Reduced

Short stature; bird like face; sun-sensitive erythema; marrow failure; leukemia; lymphoma; chromosomal instability

210900

 Immunodeficiency with centromeric instability and facial anomalies (ICF1)

Mutations in DNA methyltransferaseDNMT3B (ICF1) resulting in defective DNA methylation 602900;

AR

Decreased or normal; responses to PHA may be decreased

Decreased or normal

Hypogammaglobulinemia; variable antibody deficiency

Facial dysmorphic features; macroglossia; bacterial/opportunistic infections; malabsorption; cytopenias; malignancies; multiradial configurations of chromosomes 1, 9, 16; no DNA breaks

242860

 Immunodeficiency with centromeric instability and facial anomalies (ICF2)

Mutations in ZBTB24 (ICF2)

614064

AR

Decreased or normal;

Responses to PHA may be decreased

Decreased or normal

Hypogammaglobulinemia; variable antibody deficiency

Facial dysmorphic features; macroglossia; bacterial/opportunistic infections; malabsorption; cytopenias; malignancies; multiradial configurations of chromosomes 1, 9, 16;

614069

 PMS2 deficiency

Mutations in PMS2, resulting in Class Switch recombination deficiency due to impaired mismatch repair

600259

AR

Normal

Reduced B cells, switched and non-switched

Low IgG and IgA, elevated IgM, abnormal antibody responses

Recurrent infections; café-au-lait spots; lymphoma, colorectal carcinoma, brain tumor

276300

 RNF168 deficiency

Mutations in RNF168, resulting in defective DNA double-strand break repair (RIDDLE syndrome) 612688

AR

Normal

Normal

Low IgG, IgM, or low IgA

Short stature; mild defect of motor control to ataxia; normal intelligence to learning difficulties; mild facial dysmorphism to microcephaly; increased radiosensitivity

611943

 MCM4 deficiency

Mutations in MCM4 (minichromosome maintenance complex component 4) gene involved in DNA replication and repair

602638

AR

Normal

Normal

Normal

Viral infections (EBV, HSV, VZV)

Adrenal failure

Short stature

Low NK cells

609981

3. Thymic defects with additional congenital anomalies

 DiGeorge syndrome*

Contiguous gene deletion in chromosome 22q11.2 or mutation of a gene within this deletion region, TBX1, encoding a transcription factor critical for development of thymus and adjacent embryonic structures

602054

De novo haplo-insufficiency (majority) or AD; phenocopies may have other as yet undefined genetic lesions

Decreased or normal; 5 % have <1500 CD3 T cells/uL in neonatal period

Normal

Normal or decreased

Hypoparathyroidism, conotruncal cardiac malformation, velopalatal insufficiency, abnormal facies, intellectual disability and other abnormalities; often with 3 Mb interstitial deletion in 22q11.2 (or rarely with intragenic mutation of TBX1, deletion in 10p)

188400

 CHARGE syndrome due to CHD7 defects

Variable defects of the thymus and associated T cell abnormalities, often due to deletions or mutations in transcription regulator CHD7,

608892

De novo haplo-insufficiency (majority) or AD

Decreased or normal; response to PHA may be decreased

Normal

Normal or decreased

Coloboma, heart anomaly, choanal atresia, mental retardation, genital and ear anomalies; some are SCID-like and have low TRECs

214800

 CHARGE syndrome due to SEMA3E defects

Variable defects of the thymus and associated T cell abnormalities, often due to deletions or mutations in transcription regulator, or semaphorin SEMA3E 608166

De novo haplo-insufficiency (majority) or AD

Decreased or normal; response to PHA may be decreased

Normal

Normal or decreased

Coloboma, heart anomaly, choanal atresia, mental retardation, genital and ear anomalies; some are SCID-like and have low TRECs

214800

 Winged helix deficiency (nude)

 AAB: syndromic SCID

Defects in forkhead box N1 transcription factor encoded by FOXN1

600838

AR

Markedly decreased

Normal

Decreased

Alopecia; nail dystropphy; severe infections abnormal thymic epithelium, impaired T cell maturation

601705

4. Immune-osseous dysplasias

 Cartilage hair hypoplasia

Mutations in RMRP (RNase MRP RNA) Involved in processing of mitochondrial RNA and cell cycle control

157660

AR

Varies from severely decreased (SCID) to normal; impaired lymphocyte proliferation

Normal

Normal or reduced antibodies variably decreased

Short-limbed dwarfism with metaphysealdysostosis, sparse hair, bone marrow failure, autoimmunity, susceptibility to lymphoma and other cancers, impaired spermatogenesis, neuronal dysplasia of the intestine

250250

 Schimke

 Immunoosseous

 Dysplasia

Mutations in SMARCAL1; involved in chromatin remodeling

606622

AR

Decreased

Normal

Normal

Short stature, spondiloepiphyseal dysplasia, intrauterine growth retardation, nephropathy; bacterial, viral, fungal infections; may present as SCID; bone marrow failure

242900

5. Hyper-IgE syndromes (HIES)

 AD-HIES (Job or Buckley Syndrome)

Dominant-negative heterozygous mutations in signal transducer and activator of transcription STAT3

102582

AD

Often de novo mutation

Normal overall Th-17 and T-follicular helper cells decreased

Normal; reduced switched and non-switched memory B cells; BAFF expression increased

Elevated IgE; specific antibody production decreased

Distinctive facial features (broad nasal bridge), bacterial infections (boils and pulmonary abscesses, pneumatoceles) due to S. aureus, aspergillus, Pneumocystis jirovecii; eczema, mucocutaneous candidiasis, hyperextensible joints, osteoporosis and bone fractures, scoliosis, retention of primary teeth, aneurysm formation

147060

 Comel-Netherton syndrome

Mutations in SPINK5 resulting in lack of the serine protease inhibitor LEKTI, expressed in epithelial cells

605010

AR

Normal

Switched and non-switched B cells are reduced

Elevated IgE and IgA

Antibody variably decreased

Congenital ichthyosis, bamboo hair, atopic diathesis, increased bacterial infections, failure to thrive

256500

 PGM3 deficiency

Mutations inphosphoglycomutase 3 (PGM3) associated with a glycosylationand atopy

172100

AR

CD8 and CD4 T cells may be decreased

Reduced B and memory B cells

Normal or elevated Ig’s, elevated IgE; eosinophilia

Severe atopy, autoimmunity, bacterial and viral infections, cognitive impairment, hypomyelination

615816

6. Dyskeratosis congenita (DKC) with bone marrow failure and dysfunctional telomere maintenance

 XL-DKC due to Dyskerin deficiency

Mutations in DKC1 encoding dyskerin

300126

XL

Progressive decrease

Progressive decrease

Variable hypogammag-lobulinemia

Intrauterine growth retardation, microcephaly, nail dystrophy, 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)

305000

 AR-DKC due to nucleolar protein family A member 2 (NHP2) deficiency

Mutations in NOLA2 (NHP2),

component of the H/ACA ribonucleo-protein complex

606470

AR

Decreased

Variable

Variable

Pancytopenia, sparse scalp hair and eyelashes, prominent periorbital telangiectasia, hypoplastic/dysplastic nails

613987

 AR-DKC due to nucleolar protein family A member 3 (NHP3) or NOP10 deficiency

Mutation in NOLA3 (NOP10, PCFT), a component of the H/ACA ribonucleo-protein complex

606471

AR

Decreased

Variable

Variable

Pancytopenia, sparse scalp hair and eyelashes, prominent periorbital telangiectasia, hypoplastic/dysplastic nails

224230

 AR-DKC due to regulator of telomere elongation (RTEL1) deficiency

Mutation in RTEL1 encoding regulator of telomere elongation helicase 1 (RTEL1)

608833

AD or AR

Decreased

Variable

Variable

Pancytopenia, sparse scalp hair and eyelashes, prominent periorbital telangiectasia, hypoplastic/dysplastic nails. May present as HHS

615190

 AD-DKC due to TERC deficiency

Mutation in TERC encoding telomerase RNA component

602322

AD

Variable

Variable

Variable

Reticular hyperpigmentation of the skin, dystrophic nails, osteoporosis premalignant leukokeratosis of the oral mucosa, palmar hyperkeratosis, anemia, pancytopenia. May present as HHS

127550

 AD-DKC due to TERT deficiency

Mutation in TERT encoding telomerase reverse transcriptase 187270

AD or AR

Variable

Variable

Variable

Reticular hyperpigmentation of the skin, dystrophic nails, osteoporosis premalignant leukokeratosis of the oral mucosa, palmar hyperkeratosis, anemia, pancytopenia. AD version is milder than the AR version which can resemble HHS

613989

 AD-DKC due to TINF2 deficiency

Mutation in TINF2 encoding telomerase interacting factor 2 604319

AD

Variable

Variable

Variable

Reticular hyperpigmentation of the skin, dystrophic nails, osteoporosis premalignant leukokeratosis of the oral mucosa, palmar hyperkeratosis, anemia, pancytopenia. May present as HHS

613990

 AD/AR -DKC due to TPP1 deficiency

Mutation in adrenocortical dysplasia homolog (ACD) encoding TPP1 affecting the TELpatch domain resulting in failure to recruit telomerase to telomers

609377

AD/AR

Variable

Variable

Variable

Reticular hyperpigmentation of the skin, dystrophic nails, osteoporosis leukoplakia of the oralmucosa, carcinoma, leukemia palmar hyperkeratosis, anemia, pancytopenia. May present as HHS

 

 AR-DKC due to DCLRE1B deficiency

Mutation in DCLRE1B/ SNM1/APOLLO: DNA CROSS-LINK REPAIR PROTEIN 1B

609683

AR

   

dyskeratosis congenita and Hoyeraal-Hreidarsson (HH) syndrome

616353

 AR-DKC due to PARN deficiency

Mutation in PARN, POLYADENYLATE-SPECIFIC RIBONUCLEASE

604212

AR

    

616353

7. Defects of Vitamin B12 and Folate metabolism

 Transcobalamin 2 (TCN2) deficiency

Mutation in TCN2; encoding a transporter of cobalamin into blood cells

613441

AR

Normal

Variable

Decreased

Megaloblastic anaemia, pancytopaenia, if untreated for prolonged periods results in mental retardation

275350

 SLC46A1/PCFT deficiency causing hereditary folate malabsorbtion

Mutation in SLC46A1, encoding a proton coupled folate transporter

AR

Variable numbers and activation profile

Variable

Decreased

Megaloblastic anaemia, failure to thrive, if untreated for prolonged periods results in mental retardation

229050

611672

 Methylene-tetrahydrofolate dehydrogenase 1 (MTHFD1) deficiency

Mutations in enzyme encoded by MTHFD, essential for processing single-carbon folate derivatives

AR

Low

Low

Decreased

Megaloblastic anaemia, failure to thrive, neutropenia, seizures, mental retardation

601634

172460

8. Anhidrotic ectodermaldysplasia with immunodeficiency (EDA-ID)

 (EDA-ID. NEMO /IKBKG deficiency

Mutations of NEMO (IKBKG), a modulator of NF-κB activation

Defects in IKBKG, encoding NEMO, a component of the NF-κB pathway

Mutations of NEMO (IKBKG), a modulator of NF-κB activation

300248

XL

Normal or decreased; poor CR activation function

Normal

Low B memory B cells

Decreased; poor specific antibody responses, absent antibody to polysaccharide antigens

anhidrotic ectodermal dysplasia + specific antibody deficiency (lack of Ab response to polysac-charides) + various infections (mycobacteria and pyogens)

Various infections (bacteria, mycobacteria, viruses and fungi); colitis, EDA (not in all patients); conical teeth, variable defects of skin pigmentation, monocyte dysfunction

300291, 300584, 300301

300640

 EDA-ID IKBA gain of function mutation

Gain of function mutation in IKBA (NFKIAB), encoding IκBα, a component of the NF-κB pathway

Gain-of-function mutation of IKBA, resulting in impaired activation of NF-κB

164008

AD

Normal total T cells;; impaired TCR activation

Normal B cell numbers; impaired BCR activation;

Decreased; poor specific antibody responses, absent antibody to polysaccharide antigens

Various infections (bacteria, mycobacteria, viruses and fungi); colitis, EDA (not in all patients); variable defects of skin, hair and teeth, T cell and monocyte dysfunction

Anhidrotic ectodermal dysplasia + T cell defect + various infections: Recurrent bacterial, viral and fungal infections;

612132

9. Calcium channel defects

 ORAI-I deficiency

Mutation in ORAI1, a Ca++ release-activated channel (CRAC) modulatory component

610277

AR

Normal; defective TCR mediated activation

Normal

Normal

Autoimmunity, anhydrotic ectodermic dysplasia, non-progressive myopathy

612782

 STIM1 deficiency

Mutations in STIM1, a stromal interaction molecule 1

605921

AR

Normal; defective TCR mediated activation

Normal

Normal

Autoimmunity, anhydrotic ectodermal dysplasia, non-progressive myopathy

612783

10. Other defects

 Hepatic veno-occlusive disease with immunodeficiency (VODI)

Mutations in nuclear body protein encoded by SP110

604457

AR

Normal (decreased memory T cells)

Normal (decreased memory B cells)

Decreased IgG, IgA, IgM; absent germinal centers and tissue plasma cells

Hepatic veno-occlusive disease; Susceptibility to Pneumocystis jiroveci pneumonia, CMV, candida; thrombocytopenia; hepatosplenomegaly; cerebrospinal leukodystropy

235550

 Facial dysmorphism, immunodeficiency, livedo, short stature (FILS) syndrome

Mutation in POLE1; Defective DNA replication

174762

AR

Low naïve T cells; decreased T cell proliferation

Low memory B cells

Decreased IgM and IgG; Lack of antibodies to polysaccharide antigens

Mild facial dysmorphism (malar hypoplasia, high forehead), livedo, short stature; recurrent upper and lower respiratory tract infections, recurrent pulmonary infections and recurrent meningitis

615139

 Immunodeficiency with multiple intestinal atresias

Mutation in TTC7A (tetratricopeptide repeat (TPR) domain 7A) protein, of unkown function

609332

AR

Variable, but sometimes absent

Normal

Decreased

Multiple intestinal atresias, often with intrauterine polyhydramnios and early demise; some with SCID phenotype

243150

 Vici syndrome due to EPG5 deficiency

Mutations in EPG5 encoding ectopic P-granules autophagy protein 5, involved in the formation of autolysosomes required for autophagy

AR

Profound depletion of CD4+ cells

Defective

Decreased (particularly IgG2)

Agenesis of the corpus callosum, cataracts, cardiomyopathy, skin hypopigmentation, cleft lip/palate, recurrent infections, chronic mucocutaneous candidiasis

242840

615068

 Purine nucleoside phosphorylase (PNP) deficiency

Mutation of PNP leading to absent PNP, T cell and neurologic defects from elevated toxic metabolites, especially dGTP

164050

AR

Progressive decrease

Normal

Normal or decreased

Autoimmune haemolytic anemia, neurological impairment

613179

 HOIL1 deficiency

Mutation of HOIL1/RBCK1, encoding a component of the linear ubiquitination chain assembly complex LUBAC, resulting in impaired activation of NF-κB

610924

AR

Normal numbers,

Normal, but decreased memory B cells

Poor antibody production to polysaccharide antigens

Bacterial infections (pyogens), autoinflammation. amylopectinosis

615895

 HOIP deficiency

Mutation of HOIP1 (/RNF31), encoding a component of the linear ubiquitination chain assembly complex LUBAC, resulting in impaired activation of NF-κB

612487

AR

Normal numbers

Normal, but decreased memory B cells

decreased

Bacterial infections (pyogens), autoinflammation. Amylopectinosis, Lymphangiectasia

Not yet assigned

 Hennekam-lymphangiectasia-lymphedema syndrome

Mutation of CCBE1: (COLLAGEN AND CALCIUM-BINDING EGF DOMAIN-CONTAINING PROTEIN1)

612753

AR

Low/variable

Low/variable

decreased

Lymphangiactasia and lymphedema with facial abnormalities and other dysmorphic features

235510

 STAT5b deficiency

Mutations in STAT5B signal transducer and transcription factor, essential for normal signaling from IL-2 and 15, key growth factors for T and NK cells, as well as other cytokines

604260

AR

Modestly decreased

Normal

Normal

Growth-hormone insensitive dwarfism, dysmorphic features, eczema, lymphocytic interstitial pneumonitis, autoimmunity

245590

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

* Although TBX1 deletions are emphasized, data are lacking that demonstrate that isolated TBX1 haploinsufficiency (affecting solely the gene and none of the surrounding 22q11.2 region) explicitly causes T cell or immunologic deficiency in humans

Table 3

Predominantly antibody deficiencies

Disease

Genetic defect/Presumed pathogenesis

Gene OMIM

Inheritance

Serum Ig

Associated features

Phenotype

OMIM number

1. Severe reduction in all serum immunoglobulin isotypes with profoundly decreased or absent B cells

 BTK deficiency

Mutations in BTK, a cytoplasmic tyrosine kinase activated by crosslinking of the BCR

300300

XL

All isotypes decreased in majority of patients; some patients have detectable immunoglobulins

Severe bacterial infections; normal numbers of pro-B cells

300755

 μ heavy chain deficiency

Mutations in μ heavy chain (IGHM); essential component of the pre-BCR

147020

AR

All isotypes decreased

Severe bacterial infections; normal numbers of pro-B cells

601495

 λ5 deficiency

Mutations in λ5 (IGLL1); part of the surrogate light chain in the pre-BCR

146770

AR

All isotypes decreased

Severe bacterial infections; normal numbers of pro-B cells

613500

 Igα deficiency

Mutations in Igα (CD79A); part of the pre-BCR and BCR 112205

AR

All isotypes decreased

Severe bacterial infections; normal numbers of pro-B cells

112205

613501

 Igβ deficiency

Mutations in Igb (CD79B); part of the pre-BCR and BCR

147245

AR

All isotypes decreased

Severe bacterial infections; normal numbers of pro-B cells

612692

 BLNK deficiency

Mutations in BLNK; a scaffold protein that binds to BTK 604615

AR

All isotypes decreased

Severe bacterial infections; normal numbers of pro-B cells

613502

 PI3KR1 deficiency

Mutations in PIK3R1; a kinase involved in signal transduction in multiple cell types. Complete loss of PI3K p85-alpha resulting in complete loss of B cell development

171833

AR

All isotypes decreased

Severe bacterial infections; decreased or absent pro-B cells

615214

 E47 transcription factor deficiency

Mutations in TCF3; a transcription factor required for control of B cell development

147141

AD

All isotypes decreased

Recurrent bacterial infections

Not yet assigned

 Thymoma with immunodeficiency

Unknown

None

One or more isotypes may be decreased

Bacterial and opportunistic infections; 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-deficiency disorders

Unknown

Variable

Low IgG and IgA and/or IgM

Clinical phenotypes vary: most have recurrent infections, some have polyclonal lymphoproliferation, autoimmune cytopenias and/or granulomatous disease

 

 CD19 deficiency

Mutations in CD19; transmembrane protein that amplifies signal through BCR 107265

AR

Low IgG and IgA and/or IgM

Recurrent infections; May have glomerulonephritis

613493

 CD81 deficiency

Mutations in CD81; transmembrane protein that amplifies signal through BCR 186845

AR

Low IgG, low or normal IgA and IgM

Recurrent infections; May have glomerulonephritis

613496

 CD20 deficiency

Mutations in CD20; a B cell surface receptor involved in B cell development and plasma cell differentiation

112210

AR

Low IgG, normal or elevated IgM and IgA

Recurrent infections

613495

 CD21 deficiency

Mutations in CD21; also known as complement receptor 2 and forms part of the CD19 complex

120650

AR

Low IgG; impaired anti-pneumococcal response

Recurrent infections

614699

 TACI deficiency

Mutations in TNFRSF13B (TACI); a TNF receptor family member found on B cells and is a receptor for BAFF and APRIL

604907

AD or AR or complex

Low IgG and IgA and/or IgM

Variable clinical expression

240500

 BAFF receptor deficiency

Mutations in TNFRSF13C (BAFF-R); a TNF receptor family member found on B cells and is a receptor for BAFF

606269

AR

Low IgG and IgM;

Variable clinical expression

613494

 TWEAK deficiency

Mutations in a cytokine TWEAK (TNFSF12); TNF-related weak inducer of apoptosis

602695

AD

Low IgM and A; lack of anti-pneumococcal antibody

Pneumonia, bacterial infections, warts; thrombocytopenia. neutropenia

not yet assigned

 NFKB2 deficiency

Mutations in NFKB2; an essential component of the noncanonical NF-κB pathway

AD

Low IgG and IgA and IgM; very low B cells in some

Recurrent infections; adrenal insufficiency; ACTH deficiency; alopecia

615577

 MOGS deficiency

Mutation in mannosyl-oligosaccharide glucosidase

601336

AR

Severe hypogammaglobulinemia;

Bacterial and viral infections; severe neurologic disease; also contains glycosylation type IIb (CDG-IIb),

606056

TRNT1 deficiency

Mutation in TRNT1 a template-independent RNA polymerase required for the maturation of cytosolic and mitochondrial transfer RNAs (tRNAs) 612907

AR

B cell deficiency and hypogammaglobulinemia

congenital sideroblastic anemia; deafness; developmental delay

616084

 TTC37 deficiency

Mutation in TTC37 gene

614589

AR

Poor antibody response to pneumococcal vaccine

Recurrent bacterial and viral infections; Abnormal hair findings: trichorrhexis nodosa

222470

3. Severe reduction in serum IgG and IgA with normal/elevated IgM and normal numbers of B cells

 AID deficiency

Mutations in AICDA gene

605257

AR

IgG and IgA decreased; IgM increased

Bacterial infections; enlarged lymph nodes and germinal centers

605258

 UNG deficiency

Mutations in UNG

191525

AR

IgG and IgA decreased; IgM increased

Enlarged lymph nodes and germinal centers

608106

 INO80

INO80 chromatin remodeling complex; mild DNA repair defect 610169

AR

IgG and IgA decreased; IgM increased

Severe bacterial infections

not yet assigned

 MSH6

MSH6 gene defect part of mismatch repair [MMR] machinery); DNA repair defect

600678

AR

Variable IgG, defects; increased IgM in some; normal B cells, low switched memory B cells; Ig-CSR and SHM defects

Family or personal history of cancer

not yet assigned

4. Isotype or light chain deficiencies with generally normal numbers of B cells

 Activated PI3K-δ

Mutation in PIK3CD;p110 encoding for p110 subunit of PI3K

602839

AD gain of function

Reduced IgG2 and impaired antibody to pneumococci and hemophilus

Respiratory infections, bronchiectasis; autoimmunity; chronic EBV, CMV infection

615513

 PI3KR1 loss of function

Mutation in PIK3R1 leading to mutations in p85α

171833

AD loss of function of p85α (leading to activation of PI3K-δ – as above)

Absent IgA, low IgG

EBV, CMV viremia; growth retardation

616005

 Ig heavy chain mutations and deletions

Mutation or chromosomal deletion at 14q32

AR

One or more IgG and/or IgA subclasses as well as IgE may be absent

May be asymptomatic

 

 IGKC deficiency

Mutations in Kappa constant gene

AR

All immunoglobulins have lambda light chain

Asymptomatic

147200

 Isolated IgG subclass deficiency

Unknown

Variable

Reduction in one or more IgG subclass

Usually asymptomatic; a minority may have poor antibody response to specific antigens and recurrent viral/bacterial infections

 

 IgA with IgG subclass deficiency

Unknown

Variable

Reduced IgA with decrease in one or more IgG subclass

Recurrent bacterial infections

 

 Specific antibody deficiency with normal Ig concentrations and normal numbers of B cells

Unknown

Variable

Normal

Reduced ability to produce antibodies to specific antigens

 

 Transient hypogammaglobulinemia of infancy with normal numbers of B cells

Unknown

Variable

IgG and IgA decreased

Normal ability to produce antibodies to vaccine antigens, usually not associated with significant infections

 

 CARD 11 gain of function

CARD11; scaffold for NF-kB activity in the adaptive immune response; gain of function

AD

Congenital B cell lymphocytosis. High B cell numbers due to constitutive NF-κB activation

Splenomegaly; lymphadenopathy

607210; 606445

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. CD81 is normally co-expressed with CD19 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) include several clinical and laboratory phenotypes that may be caused by distinct genetic and/or environmental factors. 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; BTK Bruton tyrosine kinase, BLNK B cell linker protein

AID activation-induced cytidine deaminase, UNG uracil-DNA glycosylase, Ig(κ) immunoglobulin or κ light-chain type

Table 4

Diseases of immune dysregulation

Disease

Genetic defect/Presumed pathogenesis

Gene OMIM

Inheritance

Circulating T Cells

Circulating B cells

Functional defect

Associated Features

Phenotype OMIM

number

1. Familial hemophagocytic lymphohistiocytosis (FHL) syndromes

 1.1. FHL syndromes without hypopigmentation

  Perforin deficiency (FHL2)

Mutations in PRF1; perforin is a major cytolytic protein

170280

AR

Increased activated T cells

Normal

Decreased to absent NK and CTL activities cytotoxicity

Fever, Hepato-Splenomegaly (HSMG), Hemophagocytic lymphohistiocytosis (HLH), Cytopenias

603553

  (UNC13D / Munc13-4 deficiency (FHL3)

Mutations in UNC13D; required to prime vesicles for fusion

608897

AR

Increased activated T cells

Normal

Decreased to absent NK and CTL activities

(cytotoxicity and/or

degranulation)

Fever, HSMG, HLH, Cytopenias,

608898

  Syntaxin 11 deficiency, (FHL4)

Mutations in STX11, required for secretory vesicle fusion with the cell membrane

605014

AR

Increased activated T cells

Normal

Decreased NK activity (cytotoxicity and/or degranulation)

Fever, HSMG, HLH, Cytopenias,

603552

  STXBP2 / Munc18-2 deficiency (FHL5)

Mutations in STXBP2, required for secretory vesicle fusion with the cell membrane

601717

AR or AD

Increased activated T cells

Normal

Decreased NK and CTL activities (cytotoxicity and/or degranulation)

Fever, HSMG, HLH, Cytopenias,

613101

  SH2D1A deficiency (XLP1)

Mutations in SH2D1A encoding an adaptor protein regulating intracellular signaling

300490

XL

Normal or increased activated T cells

Reduced Memory B cells

partially defective NK cell and CTL cytotoxic activity

Clinical and immunologic features triggered by EBV infection: HLH, lymphoproliferation, Aplastic anaemia, lymphoma.

Hypogammaglobulinemia, absent iNKT cells

308240

  XIAP deficiency (XLP2)

Mutations in XIAP/ BIRC4 encoding an inhibitor of apoptosis

300079

XL

Normal or Increased activated T cells; low/normal iNK T cells

Normal or reduced Memory B cells

Increased T cells susceptibility to apoptosis to CD95 and enhanced activation-induced cell death (AICD)

EBV infection, Splenomegaly, lymphoproliferation HLH, Colitis, IBD, hepatitis

Low iNKT cells

300635

 1.2. FHL syndromes with hypopigmentation

  Chediak-Higashi syndrome

Mutations in LYST, impaired lysosomal trafficking

606897

AR

Increased activated T cells

Normal

Decreased NK and CTL activities (cytotoxicity and/or degranulation)

Partial albinism, recurrent infections, fever, HSMG, HLH

Giant lysosomes, neutropenia, cytopenias, bleeding tendency, progressive neurological dysfunction

214500

  Griscelli syndrome, type2

Mutations in RAB27A encoding a GTPase that promotes docking of secretory vesicles to the cell membrane

603868

AR

Normal

Normal

Decreased NK and CTL activities (cytotoxicity and/or degranulation)

Partial albinism, fever, HSMG, HLH, cytopenias

607624

  Hermansky-Pudlak syndrome, type 2

Mutations in AP3B1 gene, encoding for the β subunit of the AP-3 complex

603401

AR

Normal

Normal

Decreased NK and CTL activities (cytotoxicity and/or degranulation)

Partial albinism, recurrent infections, pulmonary fibrosis

Increased bleeding, neutropenia, HLH

608233

  Hermansky-Pudlak syndrome, type 9

Mutations in PLDN, encoding Pallidin, a component of the biogenesis of lysosome-related organelles complex-1 (BLOC-1)

604310

AR

(Not assessed; leukopenia)

(Not assessed, leukopenia)

Decreased NK cell cytolytic activity

Oculocutaneous albinism, recurrent cutaneous infections, leukopenia, thrombocytopenia

614171

2. T regulatory cells genetic defects

 IPEX, immune dysregulation, polyendocrinopathy, enteropathy X-linked

Mutations in FOXP3, encoding a T cell transcription factor

300292

XL

Normal

Normal

Lack of (and/or impaired function of) CD4+ CD25+ FOXP3+ regulatory T cells (Tregs)

Autoimmune enteropathy, early onset diabetes, thyroiditis hemolytic anemia, thrombocytopenia, eczema

Elevated IgE, IgA

304790

 CD25 deficiency

Mutations in IL2RA, encoding IL-2Rα chain, 147730

AR

Normal to decreased

Normal

No CD4 + C25+ cells with impaired function of Tregs cells

Lymphoproliferation, autoimmunity. Impaired T cell proliferation

606367

 CTLA4 deficiency (ALPSV)

Mutations in CTLA4, encoding Cytotoxic T Lymphocyte antigen 4, a protein that negatively regulate T cell receptor signaling and T cell activation.

123890

AD

Decreased

Decreased

Impaired function of Treg cells.

Autoimmune cytopenias, enteropathy, interstitial lung disease, extra-lymphoid lymphocytic infiltration recurrent infections,

616100

 STAT3 GOF mutations

Mutations in STAT3, encoding Signal Transducer and activator 3

102582

AD

Decreased

Decreased

Enhanced STAT3 signaling, leading to increased Th17 cell differentiation, lymphoproliferation and autoimmunity. Decreased Treg cell numbers and impaired phenotype

Lymphoproliferation, Solid organ autoimmunity, recurrent infections.

615952

3. Autoimmunity with or without lymphoproliferation

 APECED (APS-1), autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy

Mutations in AIRE, encoding a transcription regulator needed to establish thymic self-tolerance

607358

AR

Normal

Normal

AIRE-1 serves as check-point in the thymus for negative selection of autoreactive T cells and for generation of Tregs

Autoimmunity: hypoparathyroidism hypothyroidism, adrenal insufficiency, diabetes, gonadal dysfunction and other endocrine abnormalities, chronic mucocutaneous candidiasis, dental enamel hypoplasia, alopecia areata

Enteropathy, Pernicious anemia,

240300

 ITCH deficiency

Mutations in ITCH, an E3 ubiquitin ligase catalyzes the transfer of ubiquitin to a signaling proteins in the cell including phospholipase Cγ1 (PLCγ1)

606409

AR

Not assessed

Not assessed

Itch deficiency may cause immune dysregulation by affecting both anergy induction in auto-reactive effector T cells and generation of Tregs

Early-onset chronic lung disease (interstitial pneumonitis)

Autoimmune disorder (thyroiditis, type I diabetes, chronic diarrhea/enteropathy, and hepatitis)

Failure to thrive, developmental delay, dysmorphic facial features

613385

 Tripeptidyl-Peptidase II Deficiency

Mutations in TPP2, encoding tripeptidyl-peptidase II, serine exopeptidase involved in extralysosomal peptide degradation

190470

AR

Decreased

Decreased

TPP2 deficiency results in premature immunosenescence and immune dysregulation

Variable lymphoproliferation, severe autoimmune cytopenias, hypergammaglobulinemia, recurrent infections,

Not yet assigned

3. Autoimmune lymphoproliferative syndrome (ALPS)

 ALPS-FAS

Germinal mutations in TNFRSF6, encoding CD95/Fas cell surface apoptosis receptor**

134637

AD

AR***

Increased CD4CD8TCRαβ double negative (DN) T cells

Normal, low memory B cells

Apoptosis defect FAS mediated

Splenomegaly, adenopathies, Autoimmune cytopenias, increased lymphoma risk.

IgG and A normal or increased

Elevated FasL and IL-10, vitamin B12

601859

 ALPS-FASLG

Mutations in TNFSF6, Fas ligand for CD95 apoptosis

134638

AR

Increased DN T cells

Normal

Apoptosis defect FAS mediated

Splenomegaly, adenopathies, autoimmune cytopenias, SLE;

Soluble FasL is not elevated

601859

 ALPS-Caspase10

Mutations in CASP10, intracellular apoptosis pathway

601762

AD

Increased DN T cells

Normal

Defective lymphocyte apoptosis

Adenopathies, splenomegaly, autoimmunity.

603909

 ALPS-Caspase 8

Mutations in CASP8, intracellular apoptosis and activation pathways

601763

AR

Slightly increased DN T cells

Normal

Defective lymphocyte apoptosis and activation

Adenopathies, splenomegaly, Bacterial and viral infections,

Hypogammaglobulinemia

607271

 FADD deficiency

Mutations in FADD encoding an adaptor molecule interacting with FAS, and promoting apoptosis

602457

AR

Increased DN T cells

Normal

Defective lymphocyte apoptosis

Functional hyposplenism,

Bacterial and viral infections,

Recurrent episodes of encephalopathy and liver dysfunction.

613759

 PRKC delta deficiency

Mutations in PRKCD,

encoding a member of the protein kinase C family critical for regulation of cell survival, proliferation and apoptosis

176977

AR

Normal

Low memory B cells and

Elevation of CD5 B cells

Apoptotic defect in B cells

Recurrent infections; EBV chronic infection

Lymphoproliferation

SLE-like autoimmunity (Nephrotic and antiphospholipid syndromes)

HypoIgG

615559

4. Immune dysregulation with colitis

 IL-10 deficiency

Mutations in IL10,

encoding IL-10

124092

AR

Normal

Normal

No functional IL-10 secretion

Inflammatory bowel disease (IBD) Folliculitis,

Recurrent respiratory diseases,

Arthritis,

not assigned

 IL-10Rα deficiency

Mutations in IL10RA,

encoding IL-10R1

146933

AR

Normal

Normal

Leukocytes no response

to IL-10

IBD, Folliculitis,

Recurrent respiratory diseases,

Arthritis, Lymphoma

613148

 IL-10Rβ deficiency

Mutations in IL10RB,

encoding IL-10R2

123889

AR

Normal

Normal

Leukocytes no response

to IL-10, IL-22, IL-26, IL-28A, IL-28B, and IL-29

IBD, Folliculitis,

Recurrent respiratory diseases,

Arthritis, Lymphoma

612567

 NFAT5 haploinsufficiency

Hemizygous deletion of NFAT5

604708

AD

Normal

Normal

Decreased memory B cells and plasmablasts

IBD, recurrent sinopulmonary infections

Not yet assigned

5. Type 1 Interferonopathies

 TREX1 deficiency, Aicardi-Goutieres syndrome 1 (AGS1)

Mutations in TREX1, encoding nuclease involves in clearing cellular nucleic debris

606609

AR

AD*****

Not assessed

Not assessed

Intracellular accumulation of abnormal single-stranded (ss) DNA species leading to increased CSF alpha-IFN production

Progressive encephalopathy Intracranial calcifications,

Cerebral atrophy, leukodystrophy,

HSMG, Thrombocytopenia,

Elevated hepatic transaminases

Chronic cerebrospinal fluid (CSF) lymphocytosis

225750

 RNASEH2B deficiency, AGS2

Mutations in RNASEH2B, encoding nuclease subunit involves in clearing cellular nucleic debris

610326

AR

Not assessed

Not assessed

Intracellular accumulation of abnormal ss-DNA species leading to increased CSF alpha-IFN production

Progressive encephalopathy Intracranial calcifications,

Cerebral atrophy, leukodystrophy,

HSMG, thrombocytopenia,

Elevated hepatic transaminases

Chronic CSF lymphocytosis

610181

 RNASEH2C deficiency, AGS3

Mutations in RNASEH2C, encoding nuclease subunit involves in clearing cellular nucleic debris

610330

AR

Not assessed

Not assessed

Intracellular accumulation of abnormal ss-DNA species leading to increased CSF alpha-IFN production

Progressive encephalopathy Intracranial calcifications,

Cerebral atrophy, leukodystrophy,

HSMG, thrombocytopenia,

Elevated hepatic transaminases

Chronic CSF lymphocytosis

610329

 RNASEH2A deficienc y, AGS4

Mutations in RNASEH2A, encoding nuclease subunit involves in clearing cellular nucleic debris

606034

AR

Not assessed

Not assessed

Intracellular accumulation of abnormal ss-DNA species leading to increased CSF alpha-IFN production

Progressive encephalopathy Intracranial calcifications,

Cerebral atrophy, leukodystrophy,

HSMG, thrombocytopenia,

Elevated hepatic transaminases

Chronic CSF lymphocytosis

610333

 SAMHD1 deficiency, AGS5

Mutations in SAMHD1, encoding negative regulator of the immunostimulatory DNA response

606754

AR

Not assessed

Not assessed

Induction of the cell intrinsic antiviral response, apoptosis, and mitochondrial DNA destruction leading to increased CSF alpha-IFN production

Progressive encephalopathy Intracranial calcifications,

Cerebral atrophy, leukodystrophy,

HSMG, thrombocytopenia, anemia elevated lactates

Chronic CSF lymphocytosis,

Skin vascularitis, mouth ulcers, arthropathy

612952

 ADAR1 deficiency, AGS6

Mutations in ADAR1, encoding a RNA-specific adenosine deaminase

146920

AR

Not assessed

Not assessed

Catalyzes the deamination of adenosine to inosine in dsRNA substrates Markedly elevated CSF IFN-alpha

Progressive encephalopathy intracranial calcification,

Severe developmental delay, leukodystrophy

615010

 Aicardi-Goutieres syndrome 7 (AGS7)

IFIH1

606951

AD

Not assessed

Not assessed

IFIH1 gene encodes a cytoplasmic viral RNA receptor that activates type I interferon signaling through the MAVS adaptor molecule

Progressive encephalopathy intracranial calcification,

Severe developmental delay, leukodystrophy

615846

 Spondyloenchondro-dysplasia with immune dysregulation (SPENCD)

Mutations in ACP5, encoding tartrate-resitant acid phosphatase (TRAP)

171640

AR

Not assessed

Not assessed

Upregulation of IFN-alpha and type I IFN-stimulated genes

Recurrent bacterial and viral infections,

Intracranial calcification,

SLE-like autoimmunity (Sjögren’s syndrome, hypothyroidism, inflammatory myositis, Raynaud’s disease and vitiligo), hemolytic anemia, thrombocytopenia,

skeletal dysplasia, short stature

607944

 STING--associated vasculopathy, infantile-onset

TMEM173 encoding for STIMULATOR OF INTERFERON GENES

612374

AR

Not assessed

Not assessed

STING activates both the NF-kappa-B and IRF3 transcription pathways to induce expression of IFN-alpha and IFN-beta and exert a potent antiviral effect

Severe infantile-onset autoinfammatory vasculopathy,

615934

 ADA2 deficiency

Mutations in CECR1; encoding ADA2

607575

AR

Not assessed

Not assessed

ADAs deactivate extracellular adenosine and terminate signaling through adenosine receptors

Polyarteritis nodosa, childhood-onset, early-onset recurrent ischemic stroke and fever

615688

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. Germinal mutation and somatic 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 include in Table 9 entitled Phenocopies of PID

***** de novo dominant TREX1 mutations have been reported

Table 5

Congenital defects of phagocyte number, function, or both

Disease

Genetic defect/

Presumed pathogenesis

OMIM gene

Inheritance

Affected cells

Affected function

Associated features

Phenotype

OMIM number

1) Congenital neutropenias

 Elastase deficiency (SCN1)

Mutation in ELANE: misfolded protein response, increased apoptosis

130130

AD

N

Myeloid differentiation

Susceptibility to MDS/leukemia

202700

 GFI 1 deficiency (SCN2)

Mutation in GFI1: loss of repression of ELANE

600871

AD

N

Myeloid differentiation

B/T lymphopenia

613107

 Kostmann Disease (SCN3)

Mutation in HAX1: control of apoptosis

605998

AR

N

Myeloid differentiation

Cognitive and neurological defects in patients with defects in both HAX1 isoforms, susceptibility to MDS/leukemia

610738

 G6PC3 deficiency (SCN4)

Mutation in G6PC3: abolished enzymatic activity of glucose-6-phosphatase, aberrant glycosylation, and enhanced apoptosis of N and F

611045

AR

N + F

Myeloid differentiation, chemotaxis,

O2 production

Structural heart defects, urogenital abnormalities,

inner ear deafness, and venous angiectasias of trunks and limbs

612541

 VPS45 deficiency (SCN5)

Mutation in VPS45 controls vesicular trafficking

610035

AR

N+F

Myeloid differentiation, migration

Extramedullary hematopoiesis, bone marrow fibrosis, nephromegaly,

615285

 Glycogen storage disease

 type 1b

Mutation in G6PT1: Glucose-6-phosphate transporter 1

602671

AR

N + M

Myeloid differentiation, chemotaxis,

O2 production

Fasting hypoglycemia, lactic acidosis, hyperlipidemia, hepatomegaly

232220

 Cyclic neutropenia

Mutation in ELANE: misfolded protein response

130130

AD

N

Differentiation

Oscillations of other leukocytes and platelets

162800

 X-linked neutropenia/ myelodysplasia

Mutation in WAS: Regulator of actin cytoskeleton (loss of autoinhibition)

300392

XL, gain of function

N + M

Mitosis

Monocytopenia

300299

 P14/LAMTOR2 deficiency

Mutation in ROBLD3/LAMTOR2: Endosomal adaptor protein 14

610389

AR

N+L

Mel

Endosome biogenesis

Neutropenia

Hypogammaglobulinemia

↓CD8 cytotoxicity

Partial albinism

Growth failure

610798

 Barth Syndrome

Mutation in Tafazzin (TAZ) gene: Abnormal lipid structure of mitochondrial membrane, defective carnitine metabolism

300394

XL

N

Myeloid differentiation

Cardiomyopathy, myopathy, growth retardation

302060

 Cohen syndrome

Mutation in COH1 gene: Pg unknown 607817

AR

N

Myeloid differentiation

Retinopathy, developmental delay, facial dysmorphisms

216550

 Clericuzio syndrome

 Poikiloderma with neutropenia

Mutation in C16ORF57 (USB1), affects genomic integrity

613276

AR

N

Myeloid differentiation

Poikiloderma, MDS

604173

 JAGN1 deficiency

Mutations in JAGN1, regulates secretory pathway

616012

AR

N

Myeloid differentiation

Some with a bone phenotype

616022

 3-Methylglutaconic aciduria

Mutations in CLPB

616254

AR

N

Myeloid differentiation

Microcephaly, hypoglycemia, hypotonia, ataxia, seizures, cataracts, IUGR

Not yet assigned

 G-CSF receptor deficiency

Mutations in CSF3R, the growth factor receptor

138971

AR

N

Myeloid differentiation

Poor response to GCSF

162830

 Disease

Genetic defect/

Presumed pathogenesis

Inheritance

Affected cells

Affected function

Associated features

OMIM number

2. Defects of Motility

 Leukocyte adhesion deficiency

type 1 (LAD1)

Mutation in ITGB2: B chain for adhesion proteins CD18/CD11

600065

AR

N + M +

L + NK

Adherence,

Chemotaxis,

Endocytosis,

T/NK cytotoxicity

Delayed cord separation, skin ulcers

Periodontitis

Leukocytosis

116920

 Leukocyte adhesion deficiency type 2 (LAD2)

Mutation in SLC35C1: GDP-Fucose transporter

605881

AR

N + M

Rolling,

chemotaxis

Mild LAD type 1 features

plus hh-blood group plus mental and growth retardation

266265

 Leukocyte adhesion deficiency type 3 (LAD3)

Mutation in KINDLIN3:

Rap1-activation of β1-3 integrins

607901

AR

N + M +

L + NK

Adherence, chemotaxis

LAD type 1 plus bleeding tendency

612840

 Rac 2 deficiency

Mutation in RAC2: Regulation of actin cytoskeleton

602049

AD

N

Adherence,

chemotaxis

O2 production

Poor wound healing, leukocytosis

608203

 β-actin deficiency

Mutation in ACTB: Cytoplasmic Actin

102630

AD

N + M

Motility

Mental retardation, short stature

243310

 Localized juvenile periodontitis

Mutation in FPR1: Formylated peptide receptor

136537

AR

N

Formylpeptide induced chemotaxis

Periodontitis only

Not assigned

 Papillon-Lefèvre Syndrome

Mutation in CTSC: Cathepsin C activation of serine proteases

602365

AR

N + M

Chemotaxis

Periodontitis, palmoplantar hyperkeratosis in some patients

245000

 Specific granule deficiency

Mutation in C/EBPE: myeloid transcription factor

189965

AR

N

Chemotaxis

Neutrophils with bilobed nuclei

245480

 Shwachman-Diamond Syndrome

Mutation in SBDS: Defective ribosome synthesis607444

AR

N

Chemotaxis

Pancytopenia, exocrine pancreatic insufficiency, chondrodysplasia

260400

3. Defects of Respiratory Burst

 X-linked chronic granulomatous disease (CGD)

Mutation in CYBB: Electron transport protein (gp91phox)

300481

XL

N + M

Killing (faulty O2 production)

McLeod phenotype in patients with deletions extending into the contiguous Kell locus

306400

 Autosomal recessive CGD

Mutation in CYBA: Electron transport protein (p22phox)

608508

AR

N + M

Killing (faulty O2 production)

Infections, autoinflammatory phenotype

233690

 Autosomal recessive CGD

Mutation in NCF1: Adapter protein (p47phox)

608512

AR

N + M

Killing (faulty O2 production)

Infections, autoinflammatory phenotype

233700

 Autosomal recessive CGD

Mutation in NCF2: Activating protein (p67phox)

608515

AR

N + M

Killing (faulty O2 production)

Infections, autoinflammatory phenotype

233710

 Autosomal recessive CGD

Mutation in NCF4: Activating protein (p40 phox)

601488

AR

N + M

Killing (faulty O2 production)

Infections, autoinflammatory phenotype

613960

4. Other Defects

 GATA2 deficiency (Mono MAC syndrome)

Mutations in GATA2: loss of stem cells

137295

AD

Monocytes + peripheral DC; low NK cells

Multi lineage cytopenias

Susceptibility to Mycobacteria, papilloma viruses, histoplasmosis, alveolar proteinosis, MDS/AML/CMML

614286

614172

 Pulmonary alveolar proteinosis*

Mutation in CSF2RA

306250

Biallelic mutations in pseudoautosomal gene

Alveolar macrophages

GM-CSF signaling

Alveolar proteinosis

300770

Total no. of genes in Table 5: 31

New genes added: JAGN1, CLBP, CSF3R

Table 6

Defects in Intrinsic and Innate Immunity

Disease

Genetic defect/Presumed pathogenesis

OMIM gene

Inheritance

Affected Cell

Functional Defect

Associated Features

Phenotype

OMIM Number

1. Medelian Susceptibility to mycobacterial disease (MSMD)

 IL-12 and IL-23 receptor β1 chain deficiency

Mutation in IL12RB1: IL-12 and IL-23 receptor β1 chain

601604

AR

L + NK

IFN-γ secretion

Susceptibility to Mycobacteria and Salmonella

614891

 IL-12p40 deficiency

Mutation in IL12B : subunit p40 of IL12/IL23

161561

AR

M

IFN-γ secretion

Susceptibility to Mycobacteria and Salmonella

614890

 IFN-γ receptor 1 deficiency

Mutation in IFNGR1:

IFN-γR ligand binding chain

107470

AR

M + L

IFN-γ binding and signaling

Susceptibility to Mycobacteria and Salmonella

209950

 IFN-γ receptor 1 deficiency

Mutation in IFNGR1:

IFN-γR ligand binding chain

107470

AD

M + L

IFN-γ binding and signaling

Susceptibility to Mycobacteria and Salmonella

615978

 IFN-γ receptor 2 deficiency

Mutation in IFNGR2: IFN-γR accessory chain

147569

AR

M + L

IFN-γ signaling

Susceptibility to Mycobacteria and Salmonella

614889

 STAT1 deficiency (AD form)

Mutation in STAT1 (lost of function)

600555

AD

M + L

IFN-γsignaling

Susceptibility to Mycobacteria, Salmonella

614892

 Macrophage gp91 phox

  deficiency

Mutation in CYBB: Electron transport protein (gp 91 phox)

300481

XL

Mϕ only

Killing (faulty

O2 production)

Isolated susceptibility to mycobacteria

300645

 IRF8-deficiency (AD form)

Mutation in IRF8: IL12 production by CD1c+ MDC

601565

AD

CD1c + MDC

Differentiation of CD1c + MDC subgroup

Susceptibility to Mycobacteria

614893

 Tyk2 deficiency

Mutation in TYK2

176941

AR

Normal, but

Multiple cytokine signaling defect

Normal

Susceptibility to intracellular bacteria (Mycobacteria, Salmonella), fungi and viruses

(+/−) Elevated IgE

611521

 ISG15 deficiency

Mutation in ISG15

147571

AR

 

IFNγ defect production

Susceptibility to Mycobacteria (BCG)

Brain calcification

616126

 RORc deficiency

Mutation in RORC

602943

AR

L + NK

lack of functional RORγT protein :

IFNγ defect production

complete absence of IL-17A/F-producing T cells

mycobacteriosis and candidiasis

Not yet assigned

2. Epidermodysplasia verruciformis

 EVER1 deficiency

Mutations of TMC6

605828

AR

Keratinocytes and leukocytes

EVER proteins may be involved in the regulation of cellular zinc homeostasis in lymphocytes

HPV (group B1) infections and cancer of the skin (typical EV)

226400

 EVER2 deficiency

Mutations of TMC8

605829

AR

Keratinocytes and leukocytes

EVER proteins may be involved in the regulation of cellular zinc homeostasis in lymphocytes

HPV (group B1) infections and cancer of the skin (typical EV)

226400

 WHIM (Warts, Hypogammaglo-bulinemia, infections, Myelokathexis) syndrome

Gain-of-function mutations of CXCR4, the receptor for CXCL12

162643

AD

Granulocytes + Lymphocytes

Increased response of the CXCR4 chemokine receptor to its ligand CXCL12 (SDF-1)

warts/Human Papilloma virus (HPV) infection

Neutropenia

Reduced B cell number

Hypogammaglobulinemia

193670

4. Predisposition to severe viral infection

 STAT1 deficiency

Mutations of STAT1

600555

AR

T and NK cells and monocytes

STAT1-dependent

IFN-α, and -β response

Severe viral infections

Mycobacterial infection

613796

 STAT2 deficiency

Mutations of STAT2

600556

AR

T and NK cells

STAT2-dependent IFN-α, and -β response

Severe viral infections

(disseminated vaccine-strain measles)

Not yet assigned

 IRF7 deficiency

Mutation in IRF7

605047

AR

Leukocytes and plasmacytoid dendritic cells,

Non-hematopoietic cells

IFN-α, and -β production

IFN-λ production

Severe influenza disease

Not yet assigned

 CD16 deficiency

Mutation in CD16

146740

AR

NK cells

Deficient spontaneous NK cell cytotoxicity

Susceptibility to severe viral infections, inc. HSV, EBV, HPV

615707

5. Herpes simplex encephalitis (HSE)

 TLR3 deficiency

(b) Mutations of TLR3

603029

AD

AR

Central nervous system (CNS) resident cells and fibroblasts

TLR3-dependent

IFN-α, -β, and -λ induction

Herpes simplex virus 1 encephalitis (incomplete clinical penetrance for all etiologies listed here)

613002

 UNC93B1 deficiency

(a) Mutations of UNC93B1

608204

AR

CNS resident cells and fibroblasts

UNC-93B-dependent

IFN-α, -β, and -λ induction

Herpes simplex virus 1 encephalitis

610551

 TRAF3 deficiency

(c) Mutations of TRAF3

601896

AD

CNS resident cells and fibroblasts

TRAF3-dependent

IFN-α, -β, and -λ induction

Herpes simplex virus 1 encephalitis

614849

 TRIF deficiency

(c) Mutations of TRIF, also called TICAM1

607601

AD

AR

CNS resident cells and fibroblasts

TRIF-dependent

IFN-α, -β, and -λ induction

Herpes simplex virus 1 encephalitis

614850

 TBK1 deficiency

(c) Mutations of TBK1

604834

AD

CNS resident cells and fibroblasts

TBK1-dependent

IFN-α, -β, and -λ induction

Herpes simplex virus 1 encephalitis

Not yet assigned

6. Predisposition to invasive fungal diseases

 CARD9 deficiency

Mutations of CARD9

607212

AR

Mononuclear phagocytes

CARD9 signaling pathway

Invasive candidiasis infection

Deep dermatophytoses

212050

7. Chronic mucocutaneous candidiasis (CMC)

 IL-17RA deficiency

(a) Mutations in IL17RA

605461

AR

Epithelial cells, fibroblasts, mononuclear phagocytes

IL-17RA signaling pathway

CMC

Folliculitis

613953

 IL-17RC deficiency

Mutations in IL17RC

610925

AR

Epithelial cells, fibroblasts, mononuclear phagocytes

IL-17RC signaling pathway

CMC

Not yet assigned

 IL-17F deficiency

(b) Mutations in IL17F

606496

AD

T cells

IL-17 F-containing dimers

CMC

Folliculitis

613956

 STAT1 gain-of-function

(c) gain-of-function mutations in STAT1

600555

AD

T cells, B cells, monocytes

Gain-of-function STAT1 mutations that impair the development of IL-17-producing T cells

CMC

Various fungal, bacterial and viral (HSV) infections

Auto-immunity (Thyroiditis, diabetes, cytopenia)

Enteropathy

614162

 ACT1 deficiency

(c) Mutations in ACT1, also called TRAF3IP2

(607043)

AR

T cells, fibroblasts

Fibroblasts fail to respond to IL-17A and IL-17 F, and their T cells to IL-17E

CMC

Blepharitis, Folliculitis and macroglossia

615527

8. TLR signaling pathway deficiency

 IRAK-4 deficiency

Mutations of IRAK4, a component of TLR- and IL-1R-signaling pathway

606883

AR

Lymphocytes + Granulocytes + Monocytes

TIR-IRAK signaling pathway

Bacterial infections (pyogens)

607676

 MyD88 deficiency

Mutations of MYD88, a component of the TLR and IL-1R signaling pathway

602170

AR

Lymphocytes + Granulocytes + Monocytes

TIR-MyD88 signaling pathway

Bacterial infections (pyogens)

612260

9. Isolated congenital asplenia (ICA)

Mutations in RPSA

150370

AD

Spleen

RPSA encodes ribosomal protein SA, a component of the small subunit of the ribosome

Bacteremia (encapsulated bacteria)

No spleen

271400

8. Trypanosomiasis

Mutations in APOL- I 603743

AD

 

APOL-I

Trypanosomiasis

Not yet assigned

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/

Presumed pathogenesis

OMIN gene

Inheritance

Affected cells

Functional defects

Associated Features

Phenotype

OMIM number

1. Defects effecting the inflammasome

 Familial Mediterranean Fever

Mutations of MEFV (lead to gain of pyrin function, resulting in inappropriate IL-1β release)

608107

AR

AD

Mature granulocytes, cytokine-activated monocytes.

Decreased production of pyrin permits ASC-induced IL-1 processing and inflammation following subclinical serosal injury; macrophage apoptosis decreased.

Recurrent fever, serositis and inflammation responsive to colchicine. Predisoposes to vasculitis and inflammatory bowel disease.

249100

134610

 Mevalonate kinase deficiency (Hyper IgD syndrome)

Mutations of MVK (lead to a block in the mevalonate pathway. Interleukin-1beta mediates the inflammatory phenotype)

251170

AR

 

affecting cholesterol synthesis; pathogenesis of disease unclear

Periodic fever and leukocytosis with high IgD levels

260920

 Muckle-Wells syndrome

Mutations of NLRP3 (also called NALP3 CIAS1 or PYPAF1) (lead to constitutive activation of the NLRP3 inflammasome)

606416

AD

PMNs Monocytes

Defect in cryopyrin, involved in leukocyte apoptosis and NFkB signaling and IL-1 processing

Urticaria, SNHL, amyloidosis.

191900

 Familial cold autoinflammatory syndrome 1

Mutations of NLRP3 (See above)

606416

AD

PMNs, monocytes

same as above

Non-pruritic urticaria, arthritis, chills, fever and leukocytosis after cold exposure.

120100

 Familial cold

autoinflammatory syndrome 2

Mutations of NLRP12

609648

AD

PMNs, monocytes

same as above

Non-pruritic urticaria, arthritis, chills, fever and leukocytosis after cold exposure.

611762

 Neonatal onset multisystem

  inflammatory disease

  (NOMID) or chronic infantile

  neurologic cutaneous and

  articular syndrome (CINCA)

Mutations of NLRP3

CIAS1 (See above)

606416

AD

PMNs, chondrocytes

same as above

Neonatal onset rash, chronic meningitis, and arthropathy with fever and inflammation.

607115

 NLRC4-MAS (macrophage activating syndrome)

 Familial cold

  autoinflammatory syndrome 4

Mutation in NLRC4 (see functional defect)

606831

AD

PMNs monocytes macrophages

Gain of function mutation in NLRC4 results in elevated secretion of IL-1β and IL-18 as well as macrophage activation

Severe enterocolitis and macrophage activation syndrome

616050

616115

 PLAID (PLCγ2 associated antibody deficiency and immune dysregulation)

 Familial cold

  autoinflammatory syndrome 3

Mutation in PLCG2 ((see functional defect)

600220

AD

B cells, NK, Mast cells

Mutations cause activation of IL-1 pathways

Cold urticaria hypogammaglobulinemia

614468

 APLAID (autoinflammation and PLCγ2 associated antibody deficiency and immune dysregulation)

Mutation (c2120C > A) in PLCG2 (see function defect)

600220

AD

B cells, NK, mast cells

The mutation leads to activation of the NLRP3 inflammasome (not provoked by cold temperature)

Blistering skin lesion, pulmonary and bowel disease

614878

2. Non inflammasome-related conditions

 (TNF receptor-associated

 periodic syndrome (TRAPS)

Mutations of TNFRSF1A (resulting in increased TNF inflammatory signaling)

191190

AD

PMNs, monocytes

Mutations of 55-kD TNF receptor leading to intracellular receptor retention or diminished soluble cytokine receptor available to bind TNF

Recurrent fever, serositis, rash, and ocular or joint inflammation

142680

 Pyogenic sterile arthritis,

  pyoderma gangrenosum,

  acne (PAPA) syndrome

Mutations of PSTPIP1 (also called C2BP1) (affects both pyrin and protein tyrosine phosphatase to regulate innate and adaptive immune responses)

606347

AD

Hematopoietic tissues, upregulated in activated T-cells

Disordered actin reorganization leading to compromised physiologic signaling during inflammatory response

Destructive arthritis, inflammatory skin rash, myositis

604416

 Blau syndrome

Mutations of NOD2 (also called CARD15) (involved in various inflammatory processes)

605956

AD

Monocytes

Mutations in nucleotide binding site of CARD15, possibly disrupting interactions with lipopolysaccharides and NF-κB signaling

Uveitis, granulomatous synovitis, camptodactyly, rash and cranial neuropathies, 30 % develop Crohn’s disease

186580

 ADAM17 deletion

Mutation in ADAM17 (leads to tumor necrosis factor α converting enzyme deficiency)

603639

AR

Leukocytes and epithelial cells

Defective TNFα production

Early onset diarrhea and skin lesions

614328

 Chronic recurrent multifocal osteomyelitis and congenital

  dyserythropoietic anemia

  (Majeed syndrome)

Mutations of LPIN2 (increased expression of the proinflammatory genes)

605519

AR

Neutrophils, bone marrow cells

undefined

Chronic recurrent multifocal osteomyelitis, transfusion-dependent anemia, cutaneous inflammatory disorders

609628

 DIRA (Deficiency of the

  Interleukin 1 Receptor

  Antagonist)

Mutations of IL1RN (see functional defect)

147679

AR

PMNs, Monocytes

Mutations in the IL1 receptor antagonist allow unopposed action of Interleukin 1

Neonatal onset of sterile multifocal osteomyelitis, periostitis and pustulosis.

612852

 DITRA – Deficiency of IL-36 receptor antagonist

Mutation in IL36RN (see functional defect)

605507

AR

Keratinocyte Leukocytes

Mutations in IL-36RN leads to increase IL-8 production

Pustular Psoriasis

614204

 SLC29A3 mutation

Mutation in SLC29A3

612373

AR

Leukocyte, bone cells

Hyperpigmentation hypertrichosis

Histiocytosis-lymphadenopathy plus syndrome

602782

 CAMPS (CARD14 mediated psoriasis)

Mutation in CARD14 (see functional defect)

607211

AD

Mainly in Keratinocyte

Mutations in CARD14 activate the NF-kB pathway and production of IL-8

Psoriasis

602723

 Cherubism

Mutation in SH3BP2 (see functional defect)

602104

AD

Stroma cells, bone cells

Hyperactived macrophage and increase NF-kB

Bone degeneration in jaws

118400

 CANDLE (chronic atypical neutrophilic dermatitis with lipodystrophy)

Mutation in PSMB8,

(see functional defect)

177046

AR

Keratinocyte, B cell adipose cells

Mutations cause increase IL-6 production

Dystrophy, panniculitis

256040

 COPA defect

Mutation in COPA (Coatamer protein complex, subunit alpha)

AD

PMNs and tissues specific cells

Mutant COPA leads to defective intracellular transport via the coat protein complex I (COPI)

Autoimmune inflammatory arthritis and interstitial lung disease with Th17 dysregulation and autoantibody production

601924

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 that it is associated with activation of IL-1 pathway and 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 neurologic cutaneous and articular syndrome (CINCA) are caused by similar mutations in CIAS1/NLRP3 mutations. The disease phenotype in any individual appears to depend on modifying effects of other genes and environmental factors

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

OMIM gene

Inheritance

Laboratory features

Associated Features

Phenotype

OMIM number

1) Integral complement cascade component deficiencies

 C1q deficiency

C1QA,: Classical complement pathway component

120550

AR

Absent CH50 hemolytic activity, Defective activation of the classical pathway

Diminished clearance of apoptotic cells

SLE, infections with encapsulated organisms

613652

 C1q deficiency

C1QB: Classical complement pathway component

120570

AR

Absent CH50 hemolytic activity, Defective activation of the classical pathway

Diminished clearance of apoptotic cells

SLE, infections with encapsulated organisms

613652

 C1q deficiency

C1QC: Classical complement pathway component

120575

AR

Absent CH50 hemolytic activity, Defective activation of the classical pathway

Diminished clearance of apoptotic cells

SLE, infections with encapsulated organisms

613652

 C1r deficiency

C1R: Classical complement pathway component

613785

AR

Absent CH50 hemolytic activity, Defective activation of the classical pathway

SLE, infections with encapsulated organisms

216950

 C1s deficiency

C1S: Classical complement pathway component

120580

AR

Absent CH50 hemolytic activity

Defective activation of the classical pathway

SLE, infections with encapsulated organisms

613783

 C4 deficiency

C4A, Classical complement pathway components

120810

AR

Absent CH50 hemolytic activity, Defective activation of the classical pathway

Complete deficiency requires biallelic mutations/deletions/conversions of both C4A and C4B

SLE, infections with encapsulated organisms

614380

 C4 deficiency

C4B: Classical complement pathway components

120820

AR

Absent CH50 hemolytic activity, Defective activation of the classical pathway

Complete deficiency requires biallelic mutations/deletions/conversions of both C4A and C4B

SLE, infections with encapsulated organisms

614379

 C2 deficiency

C2: Classical complement pathway component

217000

AR

Absent CH50 hemolytic activity, Defective activation of the classical pathway

SLE, infections with encapsulated organisms, atherosclerosis

613927

 C3 deficiency

LOF

C3: Central complement component

120700

AR

Absent CH50 and AH50 hemolytic activity

Defective opsonization

Defective humoral immune response

Infections; glomerulonephritis;

Atypical Hemolytic-uremic syndrome with gain-of-function mutations.

613779

 C3 GOF

C3: Central complement component

120700

Gain-of-function AD

Increased activation of complement

Atypical Hemolytic-uremic syndrome

612925

 C5 deficiency

C5: Terminal complement component

120900

AR

Absent CH50 and AH50 hemolytic activity

Defective bactericidal activity

Neisserial infections

609536

 C6 deficiency

C6: Terminal complement component

217050

AR

Absent CH50 and AH50 hemolytic activity

Defective bactericidal activity

Neisserial infections

612446

 C7 deficiency

C7: Terminal complement component

217070

AR

Absent CH50 and AH50 hemolytic activity

Defective bactericidal activity

Neisserial infections

610102

 C8 αdeficiency

C8A: Terminal complement component

120950

AR

Absent CH50 and AH50 hemolytic activity

Defective bactericidal activity

Neisserial infections

613790

 C8γ deficiency

C8G: Terminal complement component

120930

AR

Absent CH50 and AH50 hemolytic activity

Defective bactericidal activity

Neisserial infections

613790

 C8β deficiency

C8B: Terminal complement component

120960

AR

Absent CH50 and AH50 hemolytic activity

Defective bactericidal activity

Neisserial infections

613789

 C9 deficiency

C9: Terminal complement component

120940

AR

Reduced CH50 and AP50 hemolytic activity

Deficient bactericidal activity

Mild susceptibility to Neisserial infections

613825

 MASP2 deficiency

MASP2: Cleavage of C4

605102

AR

Deficient activation of the lectin activation pathway

Pyogenic infections;

Inflammatory lung disease, autoimmunity

613791

 Ficolin 3 deficiency

FCN3: Activates the classical complement pathway

604973

AR

Absence of complement activation by the Ficolin 3 pathway.

Respiratory infections, abscesses

613860

2) Complement Regulatory defects

 C1 inhibitor deficiency

SERPING1: regulation of kinins and complement activation

606860

AD

Spontaneous activation of the complement pathway with consumption of C4/C2

Spontaneous activation of the contact system with generation of bradykinin from high molecular weight kininogen

Hereditary angioedema

106100

 Factor B

CFB: Activation of the alternative pathway

138470

AD

Gain-of-function mutation with increased spontaneous AH50

aHUS

612924

 Factor D deficiency

CFD: Regulation of the alternative complement pathway

134350

AR

Absent AH50 hemolytic activity

Neisserial infections

613912

 Properdin deficiency

CFP: Regulation of the alternative complement pathway

300383

XL

Absent AH50 hemolytic activity

Neisserial infections

312060

 Factor I deficiency

CFI: Regulation of the alternative complement pathway

217030

AR

Spontaneous activation of the alternative complement pathway with consumption of C3

Infections, Neisserial infections, aHUS, preeclampsia

610984

612923

 Factor H deficiency

CFH: Regulation of the alternative complement pathway

134370

AR/AD

Spontaneous activation of the alternative complement pathway with consumption of C3

Infections, Neisserial infections, aHUS, preeclampsia

609814

235400

 Factor H –related protein deficiencies

CFHR1-5: Bind C3b

134371

600889

605336

605337

608593

AR/AD

Normal CH50, AH50, autoantibodies to Factor H. Linked deletions of one or more CFHR genes leads to susceptibility autoantibody-mediated aHUS

aHUS, Neisserial infections

235400

 Thrombomodulin

THBD: Regulates complement and coagulant activation

188040

AD

Normal CH50, AH50

aHUS

612926

 Complement Receptor 3 (CR3) deficiency

ITGAM

120980

AR

CR3 expression is lost in LAD1. See LAD1 in Table 5

Infections

609939

 Membrane Cofactor Protein (CD46) deficiency

CD46: Dissociates C3b and C4b

120920

AD

Inhibitor of complement alternate pathway, decreased C3b binding

aHUS, infections, preeclampsia

612922

 Membrane Attack Complex Inhibitor (CD59) deficiency

CD59: Regulates the membrane attack complex formation

107271

AR

Erythrocytes highly susceptible to complement-mediated lysis

Hemolytic anemia, polyneuropathy

612300

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 syndrome (ALPS–SFAS)

Somatic mutation in TNFRSF6

Increased CD4−CD8−double negative (DN) T alpha/beta cells

Normal, but increased number of CD5+ B cells

Normal or increased

Splenomegaly, lymphadenopathy, autoimmune cytopenias

Defective lymphocyte apoptosis/ALPS–FAS (=ALPS type Im)

 RAS-associated autoimmune leukoproliferative disease (RALD)

Somatic mutation in KRAS (gain-of-function)

Normal

B cell lymphocytosis

Normal or increased

Splenomegaly, lymphadenopathy, autoimmune cytopenias, granulocytosis, monocytosis/ALPS-like

 RAS-associated autoimmune leukoproliferative disease (RALD)

Somatic mutation in NRAS (gain-of-function)

Increased CD4−CD8−double negative (DN) T alpha/beta cells

Lymphocytosis

 

Splenomegaly, lymphadenopathy, autoantibodies/ALPS-like

 Cryopyrinopathy, (Muckle-Wells /CINCA/NOMID-like syndrome)

Somatic mutation in NLRP3

Normal

Normal

Normal

Urticaria-like rash, arthropathy, neurological symptoms

Associated with autoantibodies

 Chronic mucocutaneous candidiasis (isolated or with APECED syndrome)

Germline mutation in AIRE AutoAb to IL-17 and/or IL-22

Normal

Normal

Normal

Endocrinopathy, chronic mucocutaneous candidiasis/CMC

 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 Uremic Syndrome

AutoAb to Complement Factor H

Normal

Normal

Normal

aHUS

Spontaneous activation of the alternative complement pathway

The classification this year differs in a number of ways from the previous edition published in 2014. Importantly, each defect is now listed in only one table. The diverse immunological phenotypes of many conditions imply that a very large number of conditions could very readily be listed in multiple tables. However, with the increasing number of identified defects, this would make each table large and cumbersome. For this reason, we chose to list each defect in one table only and to place it according to the most pronounced and fundamental defect. For this reason and as an example, CD40L deficiency is now found in Table 1 amongst combined immunodeficiencies, because CD40L is a T cell signaling molecule whose absence leads to both cellular and humoral defects, even though it was originally described as an antibody deficiency. Although some of our placements may be disputed, the committee came to these decisions after much thought and deliberation.

The title of Table 6 has now been slightly changed to ‘Defects in intrinsic and innate immunity’ and contains defects characterized by susceptibility to specific organisms. For this reason, the MSMDs (Mendelian Susceptibility to Mycobacterial Disease) are now in Table 6, having previously been in Table 5 (Phagocytic Disorders).

In previous editions, we have placed an asterisk against conditions in which 10 or fewer individuals had been described in the literature. However, this is now felt to be an 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 patients identified or reported.

There is a growing appreciation of wide phenotypic variability for many of the individual specific gene defects, reflecting not only the variety of mutations within each gene but also host and/or environmental modifying factors that may impact the phenotype even between individuals with the same mutation within the same gene. The complexities of these conditions in terms of clinical and immunological presentation and heterogeneity cannot easily be captured in the limited space of a table format. For this reason, the furthest right column contains the Online Mendelian Inheritance in Man (OMIM) reference for each condition to allow access to a source of greater detail and updated information as to the phenotype.

A number of the new genes included in this edition of the classification tables are molecules associated not only with the immune system, but also with more generic cellular functions; such defects result in both immunological and non-immunological abnormalities. In addition, there are a number of gain-of-function (GOF) mutations identified such as in PIK3CD. In CARD11 and STAT1 for example, there are both autosomal dominant GOF and autosomal recessive loss of function variants and these different modes of inheritance in the same gene lead to different functional consequences and hence different immunological and clinical phenotypes. The other trend that is increasingly observed is the increase in disorder of immunedysregulation rather than pure immunodeficiency.

The goal of the IUIS Expert Committee on Primary Immunodeficiencies is to increase awareness, facilitate recognition and promote optimal treatment for patients with Primary Immunodeficiencies. In addition to the current report and previous ‘classification table’ publications, the committee has also produced a ‘Phenotypic Approach for IUIS PID classification and Diagnosis: Guidelines for Clinicians at the Bedside,’ which aims to lead physicians to particular groups of PIDs starting from clinical features and combining routine immunological investigations. This will be further updated to include the newly identified defects. Together these contributions will hopefully allow a practical clinical framework for PID diagnosis.

Copyright information

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Authors and Affiliations

  • Capucine Picard
    • 1
    • 2
  • Waleed Al-Herz
    • 3
    • 4
  • Aziz Bousfiha
    • 5
  • Jean-Laurent Casanova
    • 1
    • 6
    • 7
    • 8
    • 9
  • Talal Chatila
    • 10
  • Mary Ellen Conley
    • 6
  • Charlotte Cunningham-Rundles
    • 11
  • Amos Etzioni
    • 12
  • Steven M. Holland
    • 13
  • Christoph Klein
    • 14
  • Shigeaki Nonoyama
    • 15
  • Hans D. Ochs
    • 16
  • Eric Oksenhendler
    • 17
    • 18
  • Jennifer M. Puck
    • 19
  • Kathleen E. Sullivan
    • 20
  • Mimi L K. Tang
    • 21
    • 22
    • 23
  • Jose Luis Franco
    • 24
  • H. Bobby Gaspar
    • 25
  1. 1.Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163Necker Hospital for Sick ChildrenParisFrance
  2. 2.Centre d’étude des déficits immunitaires (CEDI), Hôpital Necker-Enfants Malades, AP-HPParisFrance
  3. 3.Department of Pediatrics, Faculty of MedicineKuwait UniversityKuwait CityKuwait
  4. 4.Allergy and Clinical Immunology Unit, Department of PediatricsAl-Sabah HospitalKuwait CityKuwait
  5. 5.Clinical Immunology Unit, Casablanca Children’s Hospital, Ibn Rochd Medical SchoolKing Hassan II UniversityCasablancaMorocco
  6. 6.St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller BranchThe Rockefeller UniversityNew YorkUSA
  7. 7.Howard Hughes Medical InstituteNew YorkUSA
  8. 8.University Paris Descartes, Imagine InstituteParisFrance
  9. 9.Pediatric Hematology & Immunology UnitNecker Hospital for Sick ChildrenParisFrance
  10. 10.Division of ImmunologyChildren’s Hospital BostonBostonUSA
  11. 11.Department of Medicine and PediatricsMount Sinai School of MedicineNew YorkUSA
  12. 12.Meyer Children’s Hospital-TechnionHaifaIsrael
  13. 13.Laboratory of Clinical Infectious DiseasesNational Institute of Allergy and Infectious DiseasesBethesdaUSA
  14. 14.Dr von Hauner Children’s HospitalLudwig-Maximilians-University MunichMunichGermany
  15. 15.Department of PediatricsNational Defense Medical CollegeSaitamaJapan
  16. 16.Department of PediatricsUniversity of Washington and Seattle Children’s Research InstituteSeattleUSA
  17. 17.Department of Clinical ImmunologyHôpital Saint-Louis, Assistance Publique-Hôpitaux de ParisParisFrance
  18. 18.Université Paris Diderot, Sorbonne Paris CitéParisFrance
  19. 19.Department of PediatricsUniversity of California San Francisco and UCSF Benioff Children’s HospitalSan FranciscoUSA
  20. 20.Division of Allergy Immunology, Department of PediatricsThe Children’s Hospital of PhiladelphiaPhiladelphiaUSA
  21. 21.Murdoch Childrens Research InstituteMelbourneAustralia
  22. 22.Department of PaediatricsUniversity of MelbourneMelbourneAustralia
  23. 23.Department of Allergy and ImmunologyRoyal Children’s HospitalMelbourneAustralia
  24. 24.Group of Primary ImmunodeficienciesUniversity of AntioquiaMedellinColombia
  25. 25.UCL Institute of Child HealthLondonUK