Table 2.

CIDs with associated or syndromic features

DiseaseGenetic defectInheritanceOMIMT cellsB cellsIgAssociated features
1. Immunodeficiency with congenital thrombocytopenia 
Wiskott–Aldrich syndrome (WAS LOF) WAS XL 300392 Progressive decrease in numbers, abnormal lymphocyte responses to anti-CD3 Normal numbers Low IgM and antibody responses to polysaccharides, often high IgA and IgE Thrombocytopenia with small platelets, eczema, recurrent bacterial/viral infections, bloody diarrhea, lymphoma, autoimmune disease, IgA nephropathy. Patients with XL-thrombocytopenia have later onset of complications and more favorable life expectancy but eventually develop similar complications as observed in WAS 
WIP deficiency WIPF1 AR 602357 Reduced, defective lymphocyte responses to anti-CD3 Normal or low Normal, except for high IgE Thrombocytopenia with or without small platelets, recurrent bacterial and viral infections, eczema, bloody diarrhea; WAS protein absent 
Arp2/3-mediated filament branching defect ARPC1B AR 604223 Normal Normal numbers Normal except for high IgA and IgE Mild thrombocytopenia with normal-sized platelets, recurrent invasive infections; colitis, vasculitis, autoantibodies (ANA, ANCA), eosinophilia; defective Arp2/3 filament branching 
IKZF2 DN (ICHAD syndrome) IKZF2 AD 606234 CD4 and CD8 T-cell lymphopenia with low TRECs Normal to low Normal or low. Response to vaccine antigen normal to low Recurrent respiratory and ear infections, pneumonia, and chronic lung disease. Early-onset immune dysregulation (atopic dermatitis and AIHA) and syndromic features including developmental delay, autism, sensorineural hearing loss, cleft palate and syndromic craniofacial features, abnormal teeth, athelia (absent nipples) 
2. DNA repair defects other than those listed inTable 1  
Ataxia–telangiectasia ATM AR 607585 Progressive decrease, poor proliferation to mitogens; may have low TRECs and T cells by NBS Normal Often low IgA, IgE, and IgG subclasses, increased IgM monomers; antibodies variably decreased Ataxia, telangiectasia especially of sclerae; pulmonary infections; lymphoreticular and other malignancies; increased alpha fetoprotein; increased radiosensitivity, chromosomal instability, and chromosomal translocations 
Nijmegen breakage syndrome NBN AR 602667 Progressive decrease; may have low TRECs and T cells by NBS Variably reduced Often low IgA, IgE, and IgG subclasses, increased IgM; antibodies variably decreased Microcephaly, dysmorphic facies; lymphomas and solid tumors; increased radiosensitivity; chromosomal instability 
Bloom syndrome BLM AR 604610 Normal Normal Low Short stature, dysmorphic facies, sun-sensitive erythema; marrow failure; leukemia, lymphoma; chromosomal instability 
Immunodeficiency with centromeric instability and facial anomalies (ICF types 1, 2, 3, 4) DNMT3B AR 602900 Decreased or normal, responses to PHA may be decreased Decreased or normal Hypogammaglobulinemia or agammaglobulinemia, variable antibody deficiency Facial dysmorphic features, developmental delay, macroglossia; bacterial/opportunistic infections; malabsorption; cytopenias; malignancies; multiradial configurations of chromosomes 1, 9, 16 
ZBTB24 AR 614064 Decreased or normal Facial dysmorphic features, macroglossia; bacterial/opportunistic infections; malabsorption; cytopenias; malignancies; multiradial configurations of chromosomes 1, 9, 16 
CDCA7 AR 609937 Decreased or normal; responses to PHA may be decreased 
HELLS AR 603946 Decreased or normal 
PMS2 deficiency PMS2 AR 600259 Normal Low B cells, switched and nonswitched Low IgG and IgA, high IgM, abnormal antibody responses Recurrent infections; café-au-lait spots; lymphoma, colorectal carcinoma, brain tumors 
RNF168 deficiency (radiosensitivity, immune deficiency, dysmorphic features, learning difficulties [RIDDLE] syndrome) RNF168 AR 612688 Normal Normal Low IgG or IgA Short stature, mild defect of motor control to ataxia; normal intelligence to learning difficulties; mild facial dysmorphism to microcephaly; increased radiosensitivity 
MCM4 deficiency MCM4 AR 602638 Normal Normal Normal NK cells: low number and function; viral infections (EBV, HSV, VZV); short stature; B-cell lymphoma; adrenal failure 
X-linked reticulate pigmentary disorder (POLA1 deficiency) POLA1 XL 301220 Not assessed Not assessed Not assessed Hyperpigmentation, characteristic facies, lung, and GI involvement. NK cell dysfunction. Recurrent viral infections. POLA1 is required for synthesis of cytosolic RNA:DNA; its deficiency leads to increased type I interferon; hypomorphic variants may present with hyperpigmentation and interferonopathy, without immunodeficiency 
POLE1 (polymerase ε subunit 1) deficiency (FILS syndrome) POLE1 AR 174762 Normal; decreased T-cell proliferation Low memory B cells Low IgG2 and IgM, lack of antibody to PPS Recurrent respiratory infections, meningitis; facial dysmorphism, livedo, short stature 
POLE2 (polymerase ε subunit 2) deficiency POLE2 AR 602670 Lymphopenia, lack of TRECS at NBS, absent proliferation in response to antigens Very low Hypogammaglobulinemia Recurrent infections, disseminated BCG infections; autoimmunity (type 1 diabetes), hypothyroidism, facial dysmorphism 
Ligase I deficiency LIG1 AR 126391 Lymphopenia, increased γδ T cells, decreased mitogen response Normal Hypogammaglobulinemia, Reduced antibody responses Recurrent bacterial and viral infections; growth retardation; sun sensitivity, radiation sensitivity; macrocytic red blood cells 
NSMCE3 deficiency NSMCE3 AR 608243 Decreased number, poor responses to mitogens and antigens Normal Normal IgG, IgA, normal to elevated IgM; decreased antibody responses to PPS Severe lung disease (possibly viral); thymic hypoplasia; chromosomal breakage, radiation sensitivity 
ERCC6L2 (Hebo deficiency) ERCC6L2 AR 615667 Lymphopenia Low Normal Facial dysmorphism, microcephaly; bone marrow failure 
GINS1 deficiency GINS1 AR 610608 Low or normal Low or normal High IgA, low IgM, and IgG Neutropenia; IUGR; NK cells very low 
MCM10 deficiency MCM10 AR 619313 Low or normal Low Normal IgM, IgA, decreased IgG Severe (fatal) CMV infection, HLH-like, phenocopies GINS1 and MCM4 deficiencies; ↓ NK cells and NK function 
GINS4 deficiency GINS4 AR 610611 Normal Normal Normal or increased Low NK cell numbers and function, neutropenia, recurrent infections including CMV and varicella, and recurrent herpes labialis; recurrent otitis, sinusitis, gingivitis and oral abscesses, pneumonia, gastrointestinal sepsis, intermittent diarrhea, intrauterine growth restriction, growth delay, cryptorchidism, tonsillar hypertrophy, recurrent fever 
Rothmund–Thomson syndrome RECQL4 AR 268400 Normal or low Normal or low Normal or low Variable immunodeficiency, recurrent infections, poikiloderma, hyperkeratosis, hair, skeletal dental, and gastrointestinal abnormalities, growth delay, increased cancer risk, especially osteosarcoma 
3. Thymic defects with additional congenital anomalies 
DiGeorge/velocardiofacial syndrome
Chromosome 22q11.2DS 		Large deletion (3 Mb) typically in chromosome 22 (TBX1) AD 602054 Decreased or normal, 5% have low TRECs at NBS and <1,500 CD3T cells/μl in neonatal period Normal Normal or decreased Hypoparathyroidism; conotruncal cardiac malformation, velopalatal insufficiency, abnormal facies, intellectual disability, schizophrenia and autoimmunity 
DiGeorge/velocardiofacial syndrome Unknown Sporadic  Decreased or normal 
TBX1 deficiency TBX1 AD 602054 Decreased or normal, may have low TRECs at NBS 
CHARGE syndrome CHD7 AD 608892 Decreased or normal, may have low TRECs at NBS; response to PHA may be decreased Normal Normal or decreased Coloboma of eye; heart anomaly; choanal atresia; intellectual disability; genital and ear anomalies, CNS malformation; some are SCID-like 
SEMA3E AD 608166 
Unknown   
Winged-helix nude FOXN1 deficiency FOXN1 AR 601705 Very low Normal Decreased Severe infections; abnormal thymic epithelium, immunodeficiency; congenital alopecia, nail dystrophy; neural tube defect 
FOXN1 haploinsufficiency or GOF FOXN1 AD 600838 Severe T-cell lymphopenia at birth, normalized by adulthood Normal/low Not assessed Recurrent, viral, and bacterial respiratory tract infections; skin involvement (eczema, dermatitis), nail dystrophy 
Chromosome 10p13-p14 DS (10p13-p14DS) Del10p13-p14 AD 601362 Normal, rarely lymphopenia and decreased lymphoproliferation to mitogens and antigens; hypoplastic thymus may be present Normal Normal Hypoparathyroidism; renal disease; deafness; growth retardation; facial dysmorphism; cardiac defects may be present; recurrent infections +/- 
4. Immuno-osseous dysplasias 
Cartilage hair hypoplasia (CHH) RMRP AR 157660 Varies from severely decreased (SCID) to normal; impaired lymphocyte proliferation Normal Normal or reduced, antibodies variably decreased Short-limbed dwarfism with metaphyseal dysostosis; sparse hair; bone marrow failure; autoimmunity; susceptibility to lymphoma and other cancers; impaired spermatogenesis; neuronal dysplasia of the intestine 
Schimke immuno-osseous dysplasia SMARCAL1 AR 606622 Decreased Normal Normal Short stature, spondyloepiphyseal dysplasia, IUGR; nephropathy; bacterial, viral, fungal infections; may present as SCID; bone marrow failure 
MYSM1 deficiency MYSM1 AR 612176 T-cell lymphopenia, reduced naïve T cells, low NK cells B-cell deficiency Hypogammaglobulinemia Short stature; recurrent infections; congenital bone marrow failure, myelodysplasia; immunodeficiency affecting B cells and granulocytes; skeletal anomalies; cataracts; developmental delay 
MOPD1 deficiency (Roifman syndrome) RNU4ATAC AR 601428 Decreased NK cell function Decreased total and memory B cells Hypogammaglobulinemia, variably decreased specific antibodies Recurrent bacterial infections; lymphadenopathy; spondyloepiphyseal dysplasia, extreme IUGR; retinal dystrophy; facial dysmorphism; may present with microcephaly; short stature 
Immunoskeletal dysplasia with neurodevelopmental abnormalities (EXTL3 deficiency) EXTL3 AR 617425 Decreased Normal Decreased or normal Short stature; cervical spinal stenosis, neurodevelopmental impairment; eosinophilia; may have early infant mortality 
5. Syndromes associated with elevated IgE and/or atopic disease not listed elsewhere (hyper-IgE syndromes [HIES]) 
AD-HIES STAT3 deficiency (Job syndrome) STAT3 AD LOF (dominant negative) 147060 Normal overall; Th17, T follicular helper, MAIT, NKT cells decreased, Tregs may be increased; impaired responses to STAT3-activating cytokines Normal, reduced memory B cells, BAFF expression increased, impaired responses to STAT3-activating cytokines Very high IgE, specific antibody production decreased Distinctive facial features (broad nasal bridge); bacterial infections (boils, pulmonary abscesses, pneumatoceles) due to Staphylococcusaureus, secondary pulmonary aspergillosis, PJP; eczema, chronic mucocutaneous candidiasis (CMC); impaired acute phase response, hyperextensible joints, osteoporosis and bone fractures, scoliosis, retained primary teeth; coronary and cerebral aneurysms 
IL-6 receptor deficiency IL6R AR 147880 Normal/increased, increased memory Th2 cells; reduced proportions of cTFh cells; normal responses to mitogens Normal total and memory B; reduced switched memory B Normal/low serum IgM, IgG, A. Very high IgE; specific antibody production low Atopic dermatitis (eczema), reduced inflammatory responses, recurrent skin and lung pyogenic bacterial infections, cold abscesses; high circulating IL-6 levels 
IL-6 signal transducer (IL-6ST) partial deficiency IL6ST AR 618523 Normal Th17 cells Reduced switched and nonswitched memory B cells High IgE, specific antibody production variably affected Eczema, bacterial infections, boils, recurrent respiratory tract infections (including pneumonia, bronchiectasis) pulmonary abscesses; eosinophilia; pneumatoceles; bone fractures; retention of primary teeth; craniosynostosis; scoliosis, impaired acute phase responses 
AD 619752 Normal numbers but high naïve, low central memory T cells, and low proportion of effector memory CD8 T cells.
Increased Th2, low frequencies of TFh and MAIT 		Normal total but low memory Normal IgM, G, A; hyper-IgE Dermatitis/eczema, eosinophilia, recurrent skin infections, pneumonia, bronchiectasis, pneumatoceles with severe secondary pulmonary aspergillosis, connective tissue defects (scoliosis, face, joints, fractures, palate, tooth retention). Phenocopies aspects of AR IL-6R and IL-11R deficiencies (due to unresponsiveness to these cytokines), as well as AD STAT3 and AR ZNF341 
IL-6ST complete deficiency IL6ST AR 619751 ND; death in utero or in neonatal period occurred for most affected individuals Fatal Stuve–Wiedemann-like syndrome; skeletal dysplasia, osteoporosis, hyperextensibility, lung dysfunction, renal abnormalities, thrombocytopenia, dermatitis, eczema. Defective acute phase response. Completely unresponsive to IL-6 family cytokines 
ZNF341 deficiency
AR-HIES 		ZNF341 AR 618282 Decreased Th17 proportion and low NK cell counts
High frequencies of naïve CD4+T cells. Low frequencies of CD4+ and CD8+ CM T cells 		Normal, reduced memory B cells, impaired responses to STAT3-activating cytokines High IgE and IgG, normal or subnormal specific antibody production Phenocopy of AD-HIES; atopic dermatitis/eczema, bacterial skin infections and abscesses (S. aureus), recurrent respiratory infections, lung abscesses and pneumatoceles; CMC; mild eosinophilia; mild facial dysmorphism; skeletal/connective tissue abnormalities (hyperextensible joints; bone fractures, retention of primary teeth) 
ERBIN deficiency ERBIN AD 606944 Increased circulating Treg Normal Moderately increased IgE Recurrent respiratory infections, susceptibility to S. aureus, eczema; hyperextensible joints, scoliosis; arterial dilatation in some patients 
Loeys–Dietz syndrome (TGFBR deficiency) TGFBR1 AD 609192 Normal Normal Elevated IgE Recurrent respiratory infections; eczema, food allergies; hyperextensible joints, scoliosis, retention of primary teeth; aortic aneurisms 
TGFBR2 610168 
SMAD3 613795 
Comel–Netherton syndrome SPINK5 AR 605010 Normal Normal numbers, low switched and nonswitched B cells High IgE and IgA, antibody variably decreased Congenital ichthyosis, bamboo hair, atopic diathesis; severe atopic manifestations, increased bacterial infections; failure to thrive 
PGM3 deficiency PGM3 AR 172100 CD8 and CD4 T cells may be decreased Low B and memory B cells Normal or elevated IgG and IgA, most with high IgE, eosinophilia Severe eczema; autoimmunity; bacterial (S. aureus) and viral infections; recurrent skin abscesses, otitis media, recurrent respiratory tract infection (pneumonia, bronchiectasis); candidiasis; eosinophilia; neutropenia; skeletal anomalies/dysplasia (joint hypermotility and aneurism formation): short stature, brachydactyly, dysmorphic facial features; mild intellectual disability and cognitive impairment, delayed CNS myelination in some affected individuals. Failure to thrive 
CARD11 deficiency (heterozygous DN) CARD11 AD LOF 617638 Normal number, but defective T-cell activation and proliferation. Skewing toward Th2 Normal to low High IgE, poor specific antibody production; impaired activation of both NF-κB and mTORC1 pathways Variable atopy, eczema, food allergies, eosinophilia; cutaneous viral infections, recurrent respiratory infections; lymphoma; CID 
STAT6 GOF STAT6 AD GOF 620532 Normal numbers. T cells show Th2 skewing Normal High IgE, normal IgG Early-onset severe allergic diseases, resistant atopic dermatitis, eosinophilic GI disease with reflux, dysphagia, and eosinophilic esophagitis, food allergies with anaphylaxis, asthma with interstitial lung disease and bronchiectasis. Eosinophilia. Recurrent skin and respiratory bacterial, viral, and fungal infections in ∼50%. Short stature, skeletal features 
6. Defects of vitamin B12 and folate metabolism 
Transcobalamin 2 deficiency TCN2 AR 613441 Normal Variable Decreased Megaloblastic anemia, pancytopenia; if untreated (B12) for prolonged periods results in intellectual disability 
SLC46A1/PCFT deficiency causing hereditary folate malabsorption SLC46A1 AR 229050 Variable numbers and activation profile Variable Decreased Megaloblastic anemia, failure to thrive; if untreated for prolonged periods results in intellectual disability 
Methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) deficiency MTHFD1 AR 172460 Low thymic output, normal in vitro proliferation Low Decreased/poor antibody responses to conjugated polysaccharide antigens Recurrent bacterial infection, P. jirovecii; megaloblastic anemia; failure to thrive; neutropenia; seizures, intellectual disability; folate-responsive 
SLC19A1/PCFT deficiency causing hereditary folate malabsorption SLC19A1 AR 620603 Mitogen-induced T-cell proliferation was significantly reduced Slightly low Slightly decreased or borderline Recurrent infections, severe pneumonia, mucositis, megaloblastic folate–dependent anemia 
7. Anhidrotic ectodermodysplasia with immunodeficiency (EDA-ID) 
EDA-ID due to NEMO/IKBKG deficiency (ectodermal dysplasia, immune deficiency) IKBKG XL 300248 Normal or decreased, TCR activation impaired Normal; low memory and isotype-switched B cells Decreased, some with elevated IgA, IgM, poor specific antibody responses, absent antibodies to polysaccharide antigens Anhidrotic ectodermal dysplasia (in some); various infections (bacteria, mycobacteria, viruses, fungi); colitis; conical teeth, variable defects of skin, hair, and teeth; monocyte dysfunction 
EDA-ID due to IKBA GOF mutation NFKBIA AD GOF 164008 Normal total T cells, TCR activation impaired Normal B-cell numbers, impaired BCR activation, low memory and isotype-switched B cells Decreased IgG and IgA, elevated IgM, poor specific antibody responses, absent antibody to polysaccharide antigens Anhidrotic ectodermal dysplasia. Various infections (bacteria, mycobacteria, viruses, fungi); colitis; variable defects of skin, hair, and teeth; T-cell and monocyte dysfunction 
EDA-ID due to IKBKB GOF mutation IKBKB AD GOF 618204 Decreased T cells, impaired TCR activation Normal number, poor function Reduced Recurrent bacterial, viral, fungal infections; variable ectodermal defects 
8. Calcium channel defects 
ORAI-1 deficiency ORAI1 AR 610277 Normal, defective TCR–mediated activation Normal Normal Autoimmunity; EDA; nonprogressive myopathy 
STIM1 deficiency STIM1 AR 605921 
CRACR2A deficiency CRACR2A AR NA Mild reduction in T-cell numbers Normal Low Later onset, chronic diarrhea, recurrent lower respiratory tract infections, including pneumonia 
ITPR3 ITPR3 AR NA Low T-cell numbers, impaired T-cell activation and proliferation Low. Trend to lower proliferation Low Charcot–Marie–Tooth in one patient. CID, ITP, AIHA. Recurrent infections, enteropathy 
9. Other defects 
Purine nucleoside phosphorylase (PNP) deficiency PNP AR 164050 Progressive decrease Normal Normal or low Autoimmune hemolytic anemia; neurological impairment 
Immunodeficiency with multiple intestinal atresias TTC7A AR 609332 Variable, but sometimes absent or low TRECs at NBS; may have SCID phenotype at birth Normal or low Markedly decreased IgG, IgM, IgA Bacterial (sepsis), fungal, viral infections; multiple intestinal atresias, often with intrauterine polyhydramnios and early demise 
Trichohepatoenteric syndrome TTC37 AR 222470 Impaired IFN-γ production Variably low numbers of switched memory B cells Hypogammaglobulinemia, may have low antibody responses Respiratory infections; IUGR; facial dysmorphic features, wooly hair; early-onset intractable diarrhea, liver cirrhosis; platelet abnormalities 
SKIV2L 614602 
VODI SP110 AR 604457 Normal (decreased memory T cells) Normal (decreased memory B cells) Decreased IgG, IgA, IgM, absent germinal center and tissue plasma cells Hepatic veno-occlusive disease; susceptibility to PJP pneumonia, CMV, candida; thrombocytopenia; hepatosplenomegaly; cerebrospinal leukodystrophy 
BCL11B deficiency BCL11B AD 617237 Low, poor proliferation Normal Normal Congenital abnormalities, neonatal teeth, dysmorphic facies; absent corpus callosum, neurocognitive deficits 
EPG5 deficiency (Vici syndrome) EPG5 AR 615068 Profound depletion of CD4+ cells Defective Decreased (particularly IgG2) Agenesis of the corpus callosum; cataracts; cardiomyopathy; skin hypopigmentation; intellectual disability; microcephaly; recurrent infections, chronic mucocutaneous candidiasis 
HOIL1 deficiency RBCK1 AR 610924 Normal numbers Normal, decreased memory B cells Poor antibody responses to polysaccharides Bacterial infections; autoinflammation; amylopectinosis 
HOIP deficiency RNF31 AR 612487 Normal numbers Normal, decreased memory B cells Decreased Bacterial infections; autoinflammation; amylopectinosis; lymphangiectasia 
Hennekam lymphangiectasia–lymphedema syndrome CCBE1 AR 612753 Low/variable Low/variable Decreased Lymphangiectasia and lymphedema with facial abnormalities and other dysmorphic features 
FAT4 AR 612411 Low/variable Low/variable Decreased Lymphangiectasia and lymphedema with facial abnormalities and other dysmorphic features 
Activating de novo mutations in nuclear factor, erythroid 2–like (NFE2L2) NFE2L2 AD 617744 Not reported Decreased switched memory B cells Hypogammaglobulinemia, decreased antibody responses Recurrent respiratory and skin infections; growth retardation, developmental delay; white matter cerebral lesions; increased level of homocysteine; increased expression of stress response genes 
STAT5B deficiency STAT5B AR 245590 Modestly decreased, reduced Treg number and function Normal Hypergammaglobulinemia, increased IgE Growth hormone–insensitive dwarfism; dysmorphic features; eczema; lymphocytic interstitial pneumonitis; prominent autoimmunity 
AD (dominant negative) 604260 Normal Normal Increased IgE Growth failure; eczema (no immune defects compared with AR STAT5 deficiency) 
Kabuki syndrome
(types 1 and 2) 		KMT2D AD 602113 Normal Normal Low IgA and occasionally low IgG Typical facial abnormalities, cleft or high arched palate, skeletal abnormalities, short stature; intellectual disability; congenital heart defects; recurrent infections (otitis media, pneumonia) in 50% of patients; autoimmunity may be present 
KDM6A XL (females may be affected) 300128 
KMT2A deficiency (Wiedemann–Steiner syndrome) KMT2A AD 605130 Normal Decreased switched and nonswitched memory B cells Hypogammaglobulinemia, decreased antibody responses Respiratory infections; short stature; hypertelorism; hairy elbows; developmental delay, intellectual disability 
DIAPH1 deficiency DIAPH1 AR 616632 Reduced naïve T cells Decreased memory B cells Low IgM, normal IgG Seizures, cortical blindness, microcephaly syndrome (SCBMS); recurrent bacterial, viral, fungal infections; B lymphoma (3/7) 
AIOLOS deficiency IKZF3 AD 619437 Normal Reduced; impaired development Very low EBV susceptibility, recurrent sinopulmonary and respiratory infections, P. jirovecii, warts (HPV), Mycobacterium avium, B-cell malignancy. Haploinsufficiency shows autoimmunity and allergy 
CD28 deficiency CD28 AR 620901 Normal Normal Normal Susceptibility to HPV infection only 
SGPL1 deficiency SGPL1 AR 617575 Low Low Low maybe due to nephrotic syndrome Low or normal NK cells. Multiple bacterial infections. Nephrotic syndrome, adrenal insufficiency, ichthyosis/acanthosis, dyslipidemia, mild hypothyroidism, neurological defects 
PTCRA deficiency PTCRA AR 620931 Low T-cell counts in infancy. Total T-cell counts gradually increased to reach normal ranges. Low circulating naïve αβ T-cell counts, normal memory αβ T-cell counts and high naïve γδ T-cell counts, low TRECs Normal  Recurrent infections, lymphoproliferation, and/or autoimmunity and presence of autoantibodies. Some (6/10) individuals are healthy, and some can have small or no visible thymus. Low frequency of MAIT. High proportion of CD4−CD8−DN αβ T cells among naïve T cells 
FLT3L deficiency FLT3LG AR 620926 Normal Decreased Increased Hypoplastic anemia, monocytopenia, DC-penia, low/absence of dermal DCs. NK cells normal. Recurrent/persistent viral infections, severe warts, bacterial (pneumonia, otitis media, pharyngitis, cellulitis) and fungal infections. Recurrent diarrhea from early infancy, failure to thrive 
Chromosome 11q DS (Jacobsen syndrome) 11q23del AD 147791 Lymphopenia; low NK cells Decreased B cells and switched memory B cells Hypogammaglobulinemia, decreased antibody responses Recurrent respiratory infections; multiple warts; facial dysmorphism, growth retardation 
DiseaseGenetic defectInheritanceOMIMT cellsB cellsIgAssociated features
1. Immunodeficiency with congenital thrombocytopenia 
Wiskott–Aldrich syndrome (WAS LOF) WAS XL 300392 Progressive decrease in numbers, abnormal lymphocyte responses to anti-CD3 Normal numbers Low IgM and antibody responses to polysaccharides, often high IgA and IgE Thrombocytopenia with small platelets, eczema, recurrent bacterial/viral infections, bloody diarrhea, lymphoma, autoimmune disease, IgA nephropathy. Patients with XL-thrombocytopenia have later onset of complications and more favorable life expectancy but eventually develop similar complications as observed in WAS 
WIP deficiency WIPF1 AR 602357 Reduced, defective lymphocyte responses to anti-CD3 Normal or low Normal, except for high IgE Thrombocytopenia with or without small platelets, recurrent bacterial and viral infections, eczema, bloody diarrhea; WAS protein absent 
Arp2/3-mediated filament branching defect ARPC1B AR 604223 Normal Normal numbers Normal except for high IgA and IgE Mild thrombocytopenia with normal-sized platelets, recurrent invasive infections; colitis, vasculitis, autoantibodies (ANA, ANCA), eosinophilia; defective Arp2/3 filament branching 
IKZF2 DN (ICHAD syndrome) IKZF2 AD 606234 CD4 and CD8 T-cell lymphopenia with low TRECs Normal to low Normal or low. Response to vaccine antigen normal to low Recurrent respiratory and ear infections, pneumonia, and chronic lung disease. Early-onset immune dysregulation (atopic dermatitis and AIHA) and syndromic features including developmental delay, autism, sensorineural hearing loss, cleft palate and syndromic craniofacial features, abnormal teeth, athelia (absent nipples) 
2. DNA repair defects other than those listed inTable 1  
Ataxia–telangiectasia ATM AR 607585 Progressive decrease, poor proliferation to mitogens; may have low TRECs and T cells by NBS Normal Often low IgA, IgE, and IgG subclasses, increased IgM monomers; antibodies variably decreased Ataxia, telangiectasia especially of sclerae; pulmonary infections; lymphoreticular and other malignancies; increased alpha fetoprotein; increased radiosensitivity, chromosomal instability, and chromosomal translocations 
Nijmegen breakage syndrome NBN AR 602667 Progressive decrease; may have low TRECs and T cells by NBS Variably reduced Often low IgA, IgE, and IgG subclasses, increased IgM; antibodies variably decreased Microcephaly, dysmorphic facies; lymphomas and solid tumors; increased radiosensitivity; chromosomal instability 
Bloom syndrome BLM AR 604610 Normal Normal Low Short stature, dysmorphic facies, sun-sensitive erythema; marrow failure; leukemia, lymphoma; chromosomal instability 
Immunodeficiency with centromeric instability and facial anomalies (ICF types 1, 2, 3, 4) DNMT3B AR 602900 Decreased or normal, responses to PHA may be decreased Decreased or normal Hypogammaglobulinemia or agammaglobulinemia, variable antibody deficiency Facial dysmorphic features, developmental delay, macroglossia; bacterial/opportunistic infections; malabsorption; cytopenias; malignancies; multiradial configurations of chromosomes 1, 9, 16 
ZBTB24 AR 614064 Decreased or normal Facial dysmorphic features, macroglossia; bacterial/opportunistic infections; malabsorption; cytopenias; malignancies; multiradial configurations of chromosomes 1, 9, 16 
CDCA7 AR 609937 Decreased or normal; responses to PHA may be decreased 
HELLS AR 603946 Decreased or normal 
PMS2 deficiency PMS2 AR 600259 Normal Low B cells, switched and nonswitched Low IgG and IgA, high IgM, abnormal antibody responses Recurrent infections; café-au-lait spots; lymphoma, colorectal carcinoma, brain tumors 
RNF168 deficiency (radiosensitivity, immune deficiency, dysmorphic features, learning difficulties [RIDDLE] syndrome) RNF168 AR 612688 Normal Normal Low IgG or IgA Short stature, mild defect of motor control to ataxia; normal intelligence to learning difficulties; mild facial dysmorphism to microcephaly; increased radiosensitivity 
MCM4 deficiency MCM4 AR 602638 Normal Normal Normal NK cells: low number and function; viral infections (EBV, HSV, VZV); short stature; B-cell lymphoma; adrenal failure 
X-linked reticulate pigmentary disorder (POLA1 deficiency) POLA1 XL 301220 Not assessed Not assessed Not assessed Hyperpigmentation, characteristic facies, lung, and GI involvement. NK cell dysfunction. Recurrent viral infections. POLA1 is required for synthesis of cytosolic RNA:DNA; its deficiency leads to increased type I interferon; hypomorphic variants may present with hyperpigmentation and interferonopathy, without immunodeficiency 
POLE1 (polymerase ε subunit 1) deficiency (FILS syndrome) POLE1 AR 174762 Normal; decreased T-cell proliferation Low memory B cells Low IgG2 and IgM, lack of antibody to PPS Recurrent respiratory infections, meningitis; facial dysmorphism, livedo, short stature 
POLE2 (polymerase ε subunit 2) deficiency POLE2 AR 602670 Lymphopenia, lack of TRECS at NBS, absent proliferation in response to antigens Very low Hypogammaglobulinemia Recurrent infections, disseminated BCG infections; autoimmunity (type 1 diabetes), hypothyroidism, facial dysmorphism 
Ligase I deficiency LIG1 AR 126391 Lymphopenia, increased γδ T cells, decreased mitogen response Normal Hypogammaglobulinemia, Reduced antibody responses Recurrent bacterial and viral infections; growth retardation; sun sensitivity, radiation sensitivity; macrocytic red blood cells 
NSMCE3 deficiency NSMCE3 AR 608243 Decreased number, poor responses to mitogens and antigens Normal Normal IgG, IgA, normal to elevated IgM; decreased antibody responses to PPS Severe lung disease (possibly viral); thymic hypoplasia; chromosomal breakage, radiation sensitivity 
ERCC6L2 (Hebo deficiency) ERCC6L2 AR 615667 Lymphopenia Low Normal Facial dysmorphism, microcephaly; bone marrow failure 
GINS1 deficiency GINS1 AR 610608 Low or normal Low or normal High IgA, low IgM, and IgG Neutropenia; IUGR; NK cells very low 
MCM10 deficiency MCM10 AR 619313 Low or normal Low Normal IgM, IgA, decreased IgG Severe (fatal) CMV infection, HLH-like, phenocopies GINS1 and MCM4 deficiencies; ↓ NK cells and NK function 
GINS4 deficiency GINS4 AR 610611 Normal Normal Normal or increased Low NK cell numbers and function, neutropenia, recurrent infections including CMV and varicella, and recurrent herpes labialis; recurrent otitis, sinusitis, gingivitis and oral abscesses, pneumonia, gastrointestinal sepsis, intermittent diarrhea, intrauterine growth restriction, growth delay, cryptorchidism, tonsillar hypertrophy, recurrent fever 
Rothmund–Thomson syndrome RECQL4 AR 268400 Normal or low Normal or low Normal or low Variable immunodeficiency, recurrent infections, poikiloderma, hyperkeratosis, hair, skeletal dental, and gastrointestinal abnormalities, growth delay, increased cancer risk, especially osteosarcoma 
3. Thymic defects with additional congenital anomalies 
DiGeorge/velocardiofacial syndrome
Chromosome 22q11.2DS 		Large deletion (3 Mb) typically in chromosome 22 (TBX1) AD 602054 Decreased or normal, 5% have low TRECs at NBS and <1,500 CD3T cells/μl in neonatal period Normal Normal or decreased Hypoparathyroidism; conotruncal cardiac malformation, velopalatal insufficiency, abnormal facies, intellectual disability, schizophrenia and autoimmunity 
DiGeorge/velocardiofacial syndrome Unknown Sporadic  Decreased or normal 
TBX1 deficiency TBX1 AD 602054 Decreased or normal, may have low TRECs at NBS 
CHARGE syndrome CHD7 AD 608892 Decreased or normal, may have low TRECs at NBS; response to PHA may be decreased Normal Normal or decreased Coloboma of eye; heart anomaly; choanal atresia; intellectual disability; genital and ear anomalies, CNS malformation; some are SCID-like 
SEMA3E AD 608166 
Unknown   
Winged-helix nude FOXN1 deficiency FOXN1 AR 601705 Very low Normal Decreased Severe infections; abnormal thymic epithelium, immunodeficiency; congenital alopecia, nail dystrophy; neural tube defect 
FOXN1 haploinsufficiency or GOF FOXN1 AD 600838 Severe T-cell lymphopenia at birth, normalized by adulthood Normal/low Not assessed Recurrent, viral, and bacterial respiratory tract infections; skin involvement (eczema, dermatitis), nail dystrophy 
Chromosome 10p13-p14 DS (10p13-p14DS) Del10p13-p14 AD 601362 Normal, rarely lymphopenia and decreased lymphoproliferation to mitogens and antigens; hypoplastic thymus may be present Normal Normal Hypoparathyroidism; renal disease; deafness; growth retardation; facial dysmorphism; cardiac defects may be present; recurrent infections +/- 
4. Immuno-osseous dysplasias 
Cartilage hair hypoplasia (CHH) RMRP AR 157660 Varies from severely decreased (SCID) to normal; impaired lymphocyte proliferation Normal Normal or reduced, antibodies variably decreased Short-limbed dwarfism with metaphyseal dysostosis; sparse hair; bone marrow failure; autoimmunity; susceptibility to lymphoma and other cancers; impaired spermatogenesis; neuronal dysplasia of the intestine 
Schimke immuno-osseous dysplasia SMARCAL1 AR 606622 Decreased Normal Normal Short stature, spondyloepiphyseal dysplasia, IUGR; nephropathy; bacterial, viral, fungal infections; may present as SCID; bone marrow failure 
MYSM1 deficiency MYSM1 AR 612176 T-cell lymphopenia, reduced naïve T cells, low NK cells B-cell deficiency Hypogammaglobulinemia Short stature; recurrent infections; congenital bone marrow failure, myelodysplasia; immunodeficiency affecting B cells and granulocytes; skeletal anomalies; cataracts; developmental delay 
MOPD1 deficiency (Roifman syndrome) RNU4ATAC AR 601428 Decreased NK cell function Decreased total and memory B cells Hypogammaglobulinemia, variably decreased specific antibodies Recurrent bacterial infections; lymphadenopathy; spondyloepiphyseal dysplasia, extreme IUGR; retinal dystrophy; facial dysmorphism; may present with microcephaly; short stature 
Immunoskeletal dysplasia with neurodevelopmental abnormalities (EXTL3 deficiency) EXTL3 AR 617425 Decreased Normal Decreased or normal Short stature; cervical spinal stenosis, neurodevelopmental impairment; eosinophilia; may have early infant mortality 
5. Syndromes associated with elevated IgE and/or atopic disease not listed elsewhere (hyper-IgE syndromes [HIES]) 
AD-HIES STAT3 deficiency (Job syndrome) STAT3 AD LOF (dominant negative) 147060 Normal overall; Th17, T follicular helper, MAIT, NKT cells decreased, Tregs may be increased; impaired responses to STAT3-activating cytokines Normal, reduced memory B cells, BAFF expression increased, impaired responses to STAT3-activating cytokines Very high IgE, specific antibody production decreased Distinctive facial features (broad nasal bridge); bacterial infections (boils, pulmonary abscesses, pneumatoceles) due to Staphylococcusaureus, secondary pulmonary aspergillosis, PJP; eczema, chronic mucocutaneous candidiasis (CMC); impaired acute phase response, hyperextensible joints, osteoporosis and bone fractures, scoliosis, retained primary teeth; coronary and cerebral aneurysms 
IL-6 receptor deficiency IL6R AR 147880 Normal/increased, increased memory Th2 cells; reduced proportions of cTFh cells; normal responses to mitogens Normal total and memory B; reduced switched memory B Normal/low serum IgM, IgG, A. Very high IgE; specific antibody production low Atopic dermatitis (eczema), reduced inflammatory responses, recurrent skin and lung pyogenic bacterial infections, cold abscesses; high circulating IL-6 levels 
IL-6 signal transducer (IL-6ST) partial deficiency IL6ST AR 618523 Normal Th17 cells Reduced switched and nonswitched memory B cells High IgE, specific antibody production variably affected Eczema, bacterial infections, boils, recurrent respiratory tract infections (including pneumonia, bronchiectasis) pulmonary abscesses; eosinophilia; pneumatoceles; bone fractures; retention of primary teeth; craniosynostosis; scoliosis, impaired acute phase responses 
AD 619752 Normal numbers but high naïve, low central memory T cells, and low proportion of effector memory CD8 T cells.
Increased Th2, low frequencies of TFh and MAIT 		Normal total but low memory Normal IgM, G, A; hyper-IgE Dermatitis/eczema, eosinophilia, recurrent skin infections, pneumonia, bronchiectasis, pneumatoceles with severe secondary pulmonary aspergillosis, connective tissue defects (scoliosis, face, joints, fractures, palate, tooth retention). Phenocopies aspects of AR IL-6R and IL-11R deficiencies (due to unresponsiveness to these cytokines), as well as AD STAT3 and AR ZNF341 
IL-6ST complete deficiency IL6ST AR 619751 ND; death in utero or in neonatal period occurred for most affected individuals Fatal Stuve–Wiedemann-like syndrome; skeletal dysplasia, osteoporosis, hyperextensibility, lung dysfunction, renal abnormalities, thrombocytopenia, dermatitis, eczema. Defective acute phase response. Completely unresponsive to IL-6 family cytokines 
ZNF341 deficiency
AR-HIES 		ZNF341 AR 618282 Decreased Th17 proportion and low NK cell counts
High frequencies of naïve CD4+T cells. Low frequencies of CD4+ and CD8+ CM T cells 		Normal, reduced memory B cells, impaired responses to STAT3-activating cytokines High IgE and IgG, normal or subnormal specific antibody production Phenocopy of AD-HIES; atopic dermatitis/eczema, bacterial skin infections and abscesses (S. aureus), recurrent respiratory infections, lung abscesses and pneumatoceles; CMC; mild eosinophilia; mild facial dysmorphism; skeletal/connective tissue abnormalities (hyperextensible joints; bone fractures, retention of primary teeth) 
ERBIN deficiency ERBIN AD 606944 Increased circulating Treg Normal Moderately increased IgE Recurrent respiratory infections, susceptibility to S. aureus, eczema; hyperextensible joints, scoliosis; arterial dilatation in some patients 
Loeys–Dietz syndrome (TGFBR deficiency) TGFBR1 AD 609192 Normal Normal Elevated IgE Recurrent respiratory infections; eczema, food allergies; hyperextensible joints, scoliosis, retention of primary teeth; aortic aneurisms 
TGFBR2 610168 
SMAD3 613795 
Comel–Netherton syndrome SPINK5 AR 605010 Normal Normal numbers, low switched and nonswitched B cells High IgE and IgA, antibody variably decreased Congenital ichthyosis, bamboo hair, atopic diathesis; severe atopic manifestations, increased bacterial infections; failure to thrive 
PGM3 deficiency PGM3 AR 172100 CD8 and CD4 T cells may be decreased Low B and memory B cells Normal or elevated IgG and IgA, most with high IgE, eosinophilia Severe eczema; autoimmunity; bacterial (S. aureus) and viral infections; recurrent skin abscesses, otitis media, recurrent respiratory tract infection (pneumonia, bronchiectasis); candidiasis; eosinophilia; neutropenia; skeletal anomalies/dysplasia (joint hypermotility and aneurism formation): short stature, brachydactyly, dysmorphic facial features; mild intellectual disability and cognitive impairment, delayed CNS myelination in some affected individuals. Failure to thrive 
CARD11 deficiency (heterozygous DN) CARD11 AD LOF 617638 Normal number, but defective T-cell activation and proliferation. Skewing toward Th2 Normal to low High IgE, poor specific antibody production; impaired activation of both NF-κB and mTORC1 pathways Variable atopy, eczema, food allergies, eosinophilia; cutaneous viral infections, recurrent respiratory infections; lymphoma; CID 
STAT6 GOF STAT6 AD GOF 620532 Normal numbers. T cells show Th2 skewing Normal High IgE, normal IgG Early-onset severe allergic diseases, resistant atopic dermatitis, eosinophilic GI disease with reflux, dysphagia, and eosinophilic esophagitis, food allergies with anaphylaxis, asthma with interstitial lung disease and bronchiectasis. Eosinophilia. Recurrent skin and respiratory bacterial, viral, and fungal infections in ∼50%. Short stature, skeletal features 
6. Defects of vitamin B12 and folate metabolism 
Transcobalamin 2 deficiency TCN2 AR 613441 Normal Variable Decreased Megaloblastic anemia, pancytopenia; if untreated (B12) for prolonged periods results in intellectual disability 
SLC46A1/PCFT deficiency causing hereditary folate malabsorption SLC46A1 AR 229050 Variable numbers and activation profile Variable Decreased Megaloblastic anemia, failure to thrive; if untreated for prolonged periods results in intellectual disability 
Methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) deficiency MTHFD1 AR 172460 Low thymic output, normal in vitro proliferation Low Decreased/poor antibody responses to conjugated polysaccharide antigens Recurrent bacterial infection, P. jirovecii; megaloblastic anemia; failure to thrive; neutropenia; seizures, intellectual disability; folate-responsive 
SLC19A1/PCFT deficiency causing hereditary folate malabsorption SLC19A1 AR 620603 Mitogen-induced T-cell proliferation was significantly reduced Slightly low Slightly decreased or borderline Recurrent infections, severe pneumonia, mucositis, megaloblastic folate–dependent anemia 
7. Anhidrotic ectodermodysplasia with immunodeficiency (EDA-ID) 
EDA-ID due to NEMO/IKBKG deficiency (ectodermal dysplasia, immune deficiency) IKBKG XL 300248 Normal or decreased, TCR activation impaired Normal; low memory and isotype-switched B cells Decreased, some with elevated IgA, IgM, poor specific antibody responses, absent antibodies to polysaccharide antigens Anhidrotic ectodermal dysplasia (in some); various infections (bacteria, mycobacteria, viruses, fungi); colitis; conical teeth, variable defects of skin, hair, and teeth; monocyte dysfunction 
EDA-ID due to IKBA GOF mutation NFKBIA AD GOF 164008 Normal total T cells, TCR activation impaired Normal B-cell numbers, impaired BCR activation, low memory and isotype-switched B cells Decreased IgG and IgA, elevated IgM, poor specific antibody responses, absent antibody to polysaccharide antigens Anhidrotic ectodermal dysplasia. Various infections (bacteria, mycobacteria, viruses, fungi); colitis; variable defects of skin, hair, and teeth; T-cell and monocyte dysfunction 
EDA-ID due to IKBKB GOF mutation IKBKB AD GOF 618204 Decreased T cells, impaired TCR activation Normal number, poor function Reduced Recurrent bacterial, viral, fungal infections; variable ectodermal defects 
8. Calcium channel defects 
ORAI-1 deficiency ORAI1 AR 610277 Normal, defective TCR–mediated activation Normal Normal Autoimmunity; EDA; nonprogressive myopathy 
STIM1 deficiency STIM1 AR 605921 
CRACR2A deficiency CRACR2A AR NA Mild reduction in T-cell numbers Normal Low Later onset, chronic diarrhea, recurrent lower respiratory tract infections, including pneumonia 
ITPR3 ITPR3 AR NA Low T-cell numbers, impaired T-cell activation and proliferation Low. Trend to lower proliferation Low Charcot–Marie–Tooth in one patient. CID, ITP, AIHA. Recurrent infections, enteropathy 
9. Other defects 
Purine nucleoside phosphorylase (PNP) deficiency PNP AR 164050 Progressive decrease Normal Normal or low Autoimmune hemolytic anemia; neurological impairment 
Immunodeficiency with multiple intestinal atresias TTC7A AR 609332 Variable, but sometimes absent or low TRECs at NBS; may have SCID phenotype at birth Normal or low Markedly decreased IgG, IgM, IgA Bacterial (sepsis), fungal, viral infections; multiple intestinal atresias, often with intrauterine polyhydramnios and early demise 
Trichohepatoenteric syndrome TTC37 AR 222470 Impaired IFN-γ production Variably low numbers of switched memory B cells Hypogammaglobulinemia, may have low antibody responses Respiratory infections; IUGR; facial dysmorphic features, wooly hair; early-onset intractable diarrhea, liver cirrhosis; platelet abnormalities 
SKIV2L 614602 
VODI SP110 AR 604457 Normal (decreased memory T cells) Normal (decreased memory B cells) Decreased IgG, IgA, IgM, absent germinal center and tissue plasma cells Hepatic veno-occlusive disease; susceptibility to PJP pneumonia, CMV, candida; thrombocytopenia; hepatosplenomegaly; cerebrospinal leukodystrophy 
BCL11B deficiency BCL11B AD 617237 Low, poor proliferation Normal Normal Congenital abnormalities, neonatal teeth, dysmorphic facies; absent corpus callosum, neurocognitive deficits 
EPG5 deficiency (Vici syndrome) EPG5 AR 615068 Profound depletion of CD4+ cells Defective Decreased (particularly IgG2) Agenesis of the corpus callosum; cataracts; cardiomyopathy; skin hypopigmentation; intellectual disability; microcephaly; recurrent infections, chronic mucocutaneous candidiasis 
HOIL1 deficiency RBCK1 AR 610924 Normal numbers Normal, decreased memory B cells Poor antibody responses to polysaccharides Bacterial infections; autoinflammation; amylopectinosis 
HOIP deficiency RNF31 AR 612487 Normal numbers Normal, decreased memory B cells Decreased Bacterial infections; autoinflammation; amylopectinosis; lymphangiectasia 
Hennekam lymphangiectasia–lymphedema syndrome CCBE1 AR 612753 Low/variable Low/variable Decreased Lymphangiectasia and lymphedema with facial abnormalities and other dysmorphic features 
FAT4 AR 612411 Low/variable Low/variable Decreased Lymphangiectasia and lymphedema with facial abnormalities and other dysmorphic features 
Activating de novo mutations in nuclear factor, erythroid 2–like (NFE2L2) NFE2L2 AD 617744 Not reported Decreased switched memory B cells Hypogammaglobulinemia, decreased antibody responses Recurrent respiratory and skin infections; growth retardation, developmental delay; white matter cerebral lesions; increased level of homocysteine; increased expression of stress response genes 
STAT5B deficiency STAT5B AR 245590 Modestly decreased, reduced Treg number and function Normal Hypergammaglobulinemia, increased IgE Growth hormone–insensitive dwarfism; dysmorphic features; eczema; lymphocytic interstitial pneumonitis; prominent autoimmunity 
AD (dominant negative) 604260 Normal Normal Increased IgE Growth failure; eczema (no immune defects compared with AR STAT5 deficiency) 
Kabuki syndrome
(types 1 and 2) 		KMT2D AD 602113 Normal Normal Low IgA and occasionally low IgG Typical facial abnormalities, cleft or high arched palate, skeletal abnormalities, short stature; intellectual disability; congenital heart defects; recurrent infections (otitis media, pneumonia) in 50% of patients; autoimmunity may be present 
KDM6A XL (females may be affected) 300128 
KMT2A deficiency (Wiedemann–Steiner syndrome) KMT2A AD 605130 Normal Decreased switched and nonswitched memory B cells Hypogammaglobulinemia, decreased antibody responses Respiratory infections; short stature; hypertelorism; hairy elbows; developmental delay, intellectual disability 
DIAPH1 deficiency DIAPH1 AR 616632 Reduced naïve T cells Decreased memory B cells Low IgM, normal IgG Seizures, cortical blindness, microcephaly syndrome (SCBMS); recurrent bacterial, viral, fungal infections; B lymphoma (3/7) 
AIOLOS deficiency IKZF3 AD 619437 Normal Reduced; impaired development Very low EBV susceptibility, recurrent sinopulmonary and respiratory infections, P. jirovecii, warts (HPV), Mycobacterium avium, B-cell malignancy. Haploinsufficiency shows autoimmunity and allergy 
CD28 deficiency CD28 AR 620901 Normal Normal Normal Susceptibility to HPV infection only 
SGPL1 deficiency SGPL1 AR 617575 Low Low Low maybe due to nephrotic syndrome Low or normal NK cells. Multiple bacterial infections. Nephrotic syndrome, adrenal insufficiency, ichthyosis/acanthosis, dyslipidemia, mild hypothyroidism, neurological defects 
PTCRA deficiency PTCRA AR 620931 Low T-cell counts in infancy. Total T-cell counts gradually increased to reach normal ranges. Low circulating naïve αβ T-cell counts, normal memory αβ T-cell counts and high naïve γδ T-cell counts, low TRECs Normal  Recurrent infections, lymphoproliferation, and/or autoimmunity and presence of autoantibodies. Some (6/10) individuals are healthy, and some can have small or no visible thymus. Low frequency of MAIT. High proportion of CD4−CD8−DN αβ T cells among naïve T cells 
FLT3L deficiency FLT3LG AR 620926 Normal Decreased Increased Hypoplastic anemia, monocytopenia, DC-penia, low/absence of dermal DCs. NK cells normal. Recurrent/persistent viral infections, severe warts, bacterial (pneumonia, otitis media, pharyngitis, cellulitis) and fungal infections. Recurrent diarrhea from early infancy, failure to thrive 
Chromosome 11q DS (Jacobsen syndrome) 11q23del AD 147791 Lymphopenia; low NK cells Decreased B cells and switched memory B cells Hypogammaglobulinemia, decreased antibody responses Recurrent respiratory infections; multiple warts; facial dysmorphism, growth retardation 

EDA, ectodermal dysplasia, anhidrotic; HSV, herpes simplex virus; VZV, varicella zoster virus; BCG; bacillus Calmette–Guerin; NBS, newborn screen; TREC, T-cell receptor excision circle (biomarker for low T cells used in NBS); IUGR, intrauterine growth retardation; CID, combined immune deficiency; ITP, idiopathic thrombocytopenic purpura; AIHA, autoimmune hemolytic anemia; SCID, severe combined immunodeficiency; CID, combined immunodeficiency; CNS, central nervous system; HIES, hyper-IgE syndromes; HPV, human papillomavirus; Ab, antibody; EDA-ID, ectodermodysplasia with immunodeficiency; PJP, Pneumocystis jirovecii pneumonia.

Total number of mutant genes in Table 2: 83 including two entries for IL-6ST, two entries for STAT5B, and two for FOXN1 with distinct but partially overlapping phenotypes.

New IEIs: 10, dominant negative IKZF2, GINS4, STAT6 GOF, SMAD3, SLC19A1, SGPL1, PTCRA, FLT3L, ITPR3, and RECQL4 (33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47).

Unknown cause of DiGeorge syndrome, unknown cause of CHARGE syndrome, unknown gene(s) within 10p13-14 deletion responsible for phenotype.

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