Summary of human proximal TCR signaling defects
| TCR SS . | Gene . | Mutation . | Protein . | T cells . | B cells . | Clinical presentation . | Autoimmunity . | Infection . | Citation . | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Relative numbers . | Responsiveness . | Repertoire . | Relative numbers . | Antibodies . | ||||||||
| – – | TCRA | Homozygous p.Ser116* | Null or truncate | ↓ Total CD3+ ↓ CD4+ T ↓ CD8+ T ↓ Naive ↑ CD45RO+ | ↓ Proliferation after PHA | Abnormal Vβ | NL | NR | SCID-like disease | NR | NR | Garkaby et al., 2022 |
| – – | TCRA | Homozygous: p.Trp65* (Pt1) Homozygous: p.Arg121* (Pt2) | Null or complete LOF | ↓ Total CD3+ ↓ CD4+ TCRαβ ↓ CD8+ TCRαβ ↓ Naive ↑ γδT | None (TCR complex does not form) | Mostly γδT, few αβ, limited TRAV | NL | ↑ IgG (Pt1) ↑ IgA (Pt1, 2, 3) ↔ IgM (Pt1, 2, 3) ↑ IgE (Pt1, 2, 3) | SCID | NR | CMV (Pt1) BCG (Pt1, 2) Salmonella and oral thrush (Pt2) | Materna et al., 2025 |
| −/+ | TCRA | Homozygous: p.Thr107LeufsX56 | Partial deficiency | ↓ CD4+ TCRαβ ↓ CD8+ TCRαβ ↓ Naive ↑ γδT | ↓ Proliferation after PHA, anti-CD3, or PWM (mislocalized TCR) | Mostly γδT, few αβ | NL | NL (total Ig subtypes) NL (tetanus, pneumo, and Hib) ↑ IgE-Pt1 | CID: Recurrent respiratory tract infections, otitis media, candidiasis, diarrhea, and failure to thrive | Hypereosinophilia, low-titer antinuclear antibodies (ANA), vitiligo, and alopecia areata (Pt1) Hypereosinophilia, eczema, autoimmune hemolytic anemia, anti-lymphocyte antibodies, anti-TTG antibodies, low-titer ANA, and pityriasis rubra pilaris (Pt2) | Cryptosporidium Staphylococcus aureus Streptococcus pneumoniae Pseudomonas Rotavirus Salmonella enterica Varicella zoster | Morgan et al., 2011 |
| −/+ | TCRA | Homozygous: p.Thr107LeufsX56 | Partial deficiency | ↓ Total CD3+ ↓ CD4+ TCRαβ ↓ CD8+ TCRαβ ↓ Naive ↑ γδT | NR Mislocalized TCR | Mostly γδT, few αβ, and limited TRAV | ↓ B | ↑ IgG (Pt1) ↑ IgA (Pt1–3) ↔ IgM (Pt1–3) ↑ IgE (Pt1–3) | CID: Recurrent lower respiratory tract infections, lymphoproliferation, warts, and mimics DOCK8 deficiency | No autoimmunity | Lower respiratory tract infections and EBV (Pt3) | Rawat et al., 2021 |
| – – | CD3D | Homozygous: p.R68X | Null or complete LOF | ↓ Total CD3+ ↓ CD4+ TCRαβ ↓ CD8+ TCRαβ ↓ Naive ↑ γδT | ↓ Proliferation after PHA | NR | NL | NL Total Ig | SCID: Fever, tachypnea, tachycardia, respiratory arrest, chronic diarrhea, respiratory distress, lethargy, and jaundice | NR | Adenovirus (Pt2) CMV (Pt3) | Dadi et al., 2003 |
| – – | CD3D | Homozygous: p.Trp43* (with BTK LOF mutation) | Null | ↓ Total CD3+ ↓ CD4+ T ↓ CD8+ T | NR | NR | NL | Hypogammagloblunemia due to concurrent BTK mutation | SCID | NR | Rotavirus BCGosis due to vaccination Oral thrush (Pt2) | Al-Hammadi et al., 2020 |
| – – | CD3D | Homozygous: p.C93X (Pt1) Homozygous: p.R68X (Pt2) | Truncate | ↓ Total CD3+ ↓ CD4+ T ↓ CD8+ T | NR (Pt1) ↓ Proliferation (Pt2) | NR | NL | NR | SCID (T−B+NK+) | NR | NR | de Saint Basile et al., 2004 |
| – – | CD3D | Homozygous: c.56-1G>T Exon 1 skipping | Truncate | ↓ Total CD3+ ↓ CD4+ T ↓ CD8+ T | NR | NR | NL | ↓ IgG ↓ IgA ↓ IgM | SCID: Failure to thrive | NR | Recurrent sinopulmonary infections and candidiasis, BCG lymphadenitis | Sonmez et al., 2025 |
| – – | CD3D | Homozygous: p.S53X (Pt1) Homozygous: c.IVS2-2A>G (Pt2) | Truncate or null (Pt1) Truncate (Pt2) | ↓ Total CD3+ ↓ CD4+ TCRαβ ↓ CD8+ TCRαβ ↓ Naive ↑ γδT | NR | NR | NL (Pt1) ↑ B (Pt2) | ↓ IgG (Pt1) ↓ IgA (Pt1) ↑ IgE (Pt2) | SCID: Failure to thrive | NR (Pt1) Eczema (Pt2) Omen syndrome (Pt2) | Recurrent pneumonia Septicemia Candida (Pt2) | Vignesh et al., 2021 |
| – – | CD3D | Homozygous: c.IVS2-2A>G mRNA lacks exon3 | Truncate | ↓ Total CD3+ | NR | NR | NL (Pt1) ↑ B (Pt2) | ↓ IgG (Pt1) ↓ IgA (Pt1) ↑ IgE (Pt2) | SCID | NR | CMV, pneumonitis (Pt1); oral thrush (Pt2) | Takada et al., 2005 |
| – | CD3D | Homozygous: c.IVS2+5G>A G>A at position +5 in the 5′ splice donor site of intron 2 (in frame exon 2 deletion) | Truncate | ↓ Total CD3+ ↓ CD4+ TCRαβ ↓ CD8+ TCRαβ ↓ Naive ↑ γδT | ↓ CD25/CD69 upregulation upon activation | NR | NL | ↔ IgG ↔ IgA ↑ IgE (Pt1) Antibody response to protein antigens impaired (Pt1) Hypogammagloblunemia (Pt2) | Leaky SCID: Failure to thrive, severe diarrhea, prostrating diarrhea, respiratory distress, discrete lymphopenia, severe hypogammaglobulinemia, and protein-losing enteropathy | Hyper-IgE Eosinophilia Atopic dermatitis (all Pt1) | Pt1: Bronchopneumonia Salmonella, Campylobacter, Cryptosporidium, oral candidiasis (Pt1) Urine CMV, nasal adenovirus (Pt2) | Gil et al., 2011 |
| – | CD3G | Homozygous: c.80-1G>C Splice-acceptor variant causing aberrant splicing with a 17-bp exonic deletion and frameshift (IVS2-1G>C) | Null | ↓ CD3 T NL CD4+ T ↓ CD8+ T ↓ Naive T ↑ Memory T | NR | NR | NR | Selective Ig2 deficiency (Pt1) NL Antibody responses to protein antigens | SCID (with features of autoimmunity): Failure to thrive, intractable diarrhea, autoimmune hemolytic anemia, mild respiratory distress, asthma | Serum autoantibodies against mitochondria, smooth muscle, and intestinal epithelial cells Severe autoimmune hemolytic anemia and respiratory distress Autoimmune enteropathy with gut epithelial cell autoantibodies (Pt1) Asthma, vitiligo, and atopic eczema (Pt2) | Repeated gram-positive and negative bacterial infections, viral pneumonia, parainfluenza 3 (Pt1), Hecht’s pneumonia (Pt2) | Arnaiz-Villena et al., 1992; Allende et al., 2000 |
| −/+ | CD3G | Homozygous: c.1A > G p.translation start change | Null or complete LOF | NL Total CD3+ ↓ CD4+ TCRαβ ↓ Naive ↑ Memory T ↓ Treg | ↓ Proliferation after PHA, Con-A, or anti-CD3 | Reduced diversity | ↓ All memory B | Hypogammaglobulinemia Impaired vaccination response to Haemophilus influenzae type B and Pneumococcus | CID with autoimmunity | GLILD Autoimmune enteropathy AIHA | EBV Clostridioides difficile Klebsiella pneumoniae | Delmonte et al., 2021 |
| + | CD3G | Homozygous: c.del213A p.Asn71Metfs*110 | Null or complete LOF | NR Treg NL | NL Proliferation after PHA | NR | ↓ Switched memory B ↓ CD40L | Hypogammaglobulinemia ↓ IgG ↓ IgA ↓ IgM ↓ IgE | CVID: Without recognizable autoimmunity | NR | Recurrent sinopulmonary infections without opportunistic infections | Lee et al., 2019 |
| − | CD3G | Homozygous: p.K69X | Complete LOF | Mild αβ and γδ T lymphocytopenia | ↓ Proliferation after PHA or antigens (low CD3 expression) | NR | NL | NL | SCID: Chronic diarrhea (Pt1, 2) | Psoriasis, low titer microsomal and thyroglobulin autoantibodies (Pt3) | Pulmonary infections, recurrent otitis media, oral thrush, severe diaper dermatitis, and perianal fistula (Pt1) Oral thrush, perianal fistula (Pt2) | Recio et al., 2007 |
| + | CD3G | Homozygous: p.K69X | Truncate | ↓ Total CD3+ ↓ CD4+ | NR low CD3 expression | NR | NL | NL Ig ↓ IgA | CID with autoimmunity | Psoriasis Asthma | Upper/lower respiratory tract infections VZV infection | Sonmez et al., 2025 |
| + | CD3G | Homozygous: p.Lys71fs | Truncate | ↓ Total CD3+ NL CD4+ ↓ CD8+ ↓ Naive ↑ Memory ↓ Treg | NR | NR | ↑ Naive B ↑ Memory B | Positive ANA, high IgE | Lupus-like disease: With immunodeficiency | Autoimmune thyroiditis AIHA ITP Asthma | Recurrent respiratory infections, sinusitis, and latent tuberculosis infection | Lin et al., 2024 |
| + + | CD3G | Homozygous: c.80-1G>C | Splice variant-reduced expression | ↓ Total CD3+ ↓ CD4+ ↓ CD8+ ↓ Naive (except Pt1) ↓ γδT | NR | NR | NL | ↑ IgG (Pt1, 4) ↓ IgA (Pt3, 4) ↓ IgM (Pt4) ↑ IgE (Pt1, 2) Low anti-HBs titer (Pt4) | CID (T−B+NK+) | Diffuse vitiligo (Pt1) Autoimmune thyroiditis (Pt1–5) Atopic dermatitis/pityriasis alba (Pt2) Autoimmune hepatitis (Pt4) Autoimmune hemolytic anemia (Pt4, 5) Immune thrombocytopenic purpura (Pt4) | Recurrent upper and lower respiratory tract infections VZV Candida albicans Giardia intestinalis | Gokturk et al., 2014; Tokgoz et al., 2013 |
| + + | CD3G | Homozygous: c.1A>G (Pt1) Homozygous: c.80-1G>C (Pt2–5) Compound: c.1A>G /c.80-1G>C (Pt6) | Reduced surface expression | NL (Pt1, 4, 5, 6) ↓ Total CD3+ (Pt2, 3) NL CD4+ NL CD8+ ↑ Memory ↑ TEMRA ↑ Exhausted CD8+ ↓ Treg | ↓ Proliferation after PHA ↓ CD25 after anti-CD3/28 | Skewed use of TRBV and TRBJ | NR | NL for most ↓ IgG (Pt4) ↓ IgA (Pt4) | Immunodeficiency with autoimmunity | Autoimmune enteropathy, GLILD, AIHA (Pt1) Hypothyroidism (Pt2, 3, 4, 6) AIHA, ITP, nephropathy, ALPS (Pt4) Thyroiditis (Pt5) Vitiligo (Pt6) | Klebsiella pneumoniae, MSSA, severe EBV (Pt1) Acute bronchitis (Pt2) RRTI, bronchiectasis (Pt4) Soft tissue abscesses, viral meningitis (Pt6) | Rowe et al., 2018 |
| − − | CD3E | c.fs43 Creates stop 13 residues downstream p.extracellular domain only | Null | ↓ Total CD3+ ↓ CD4+ ↓ CD8+ | NR | NR | NL | ↓ IgA (Pt2) ↓ IgM (Pt2) | SCID | NR | Pneumonitis, oral candidiasis, disseminated CMV infection | de Saint Basile et al., 2004 |
| − − | CD3E | NR | Null | ↓ Total CD3+ ↓ CD4+ | Absence of T cell proliferation, following PHA anti-CD3 and anti-CD2 antibody-triggered T cell activation | NR | NR | NR | SCID | NR | Recurrent lung infections | Thoenes et al., 1990; Thoenes et al., 1992 |
| − − | CD3E | Homozygous: p.Y96X (Pt1) Homozygous: c.352 + 1G>A (Pt2) | Truncate (Pt1) Splice variant (Pt2) | ↓ Total CD3+ (Pt1) | NR | NR | ↑ B | ↓ IgG (Pt1, 2) ↓ IgA (Pt1, 2) ↓ IgM (Pt1) | SCID: Persistent diarrhea | NR | Recurrent pneumonia Disseminated BCGosis (Pt1) Tuberculosis and Pseudomonas (Pt2) | Vignesh et al., 2021 |
| − − | CD3E | Homozygous: c.fs*9 p.L58H | Truncate | ↓ Total CD3+ ↓ CD4+ ↓ CD8+ ↓ Treg | NR | NR | ↑ B | ↓ IgG (Pt1, 2) ↓ IgA (Pt1, 2) ↓ IgM (Pt1) | SCID (T−B+NK+): ARDS, diarrhea | NR | Sepsis CMV (Pt1) Pneumonitis, oral candidiasis (Pt2) | Firtina et al., 2017 |
| − − | CD3E | Homozygous: c.567 + 42_567 + 73del | Null-mRNA stability compromised | ↓ Total CD3+ ↓ CD4+ ↓ CD8+ | NR | NR | NL | ↓ IgG (Pt1) ↓ IgA (Pt1, 2) ↓ IgM (Pt1) | SCID: Fever | NR (Pt1) Autoimmune hepatitis (Pt2) | Oral candidiasis, lung infection (Pt1) Persistent candidiasis, CMV, pneumonia (Pt2) | Sonmez et al., 2025 |
| − | CD3E | Homozygous: c.IVS7DS, T-C, +2 p.W59X | Truncate-reduced expression | ↓ Total CD3+ ↓ CD4+ ↓ CD8+ | Absence of T cell proliferation, CD25 expression, and calcium flux after anti-CD3 and anti-CD2 | NR | NL | NL Total IgA Defective poliovirus or isohemagglutinin IgA | CID: Recurrent pneumonia | NR | Hemophilus influenzae Recurrent otitis media | Soudais et al., 1993; Le Deist et al., 1991 |
| −− | CD3Z | Homozygous: p.D138fsX272 eliminates ITAM3 | Null | ↓ Total CD3+ ↓ CD4+ ↓ CD8+ | ↓ Proliferation after PHA, Con A, PWM, Candida, anti-CD3ε, autologous cells, or allogeneic cells | Oligoclonal | NL | Pre-IVIG values not available | SCID (T−B+NK+): Failure to thrive, chronic cough, chronic mild rash, gastroenteritis | No definitive autoimmunity, but some symptoms | CMV Salmonella gastroenteritis Recurrent otitis media | Roberts et al., 2007 |
| + + | CD3Z | Heterozygous: p.Y152X and p.Q101X ITAM3 eliminated | Dominant negative | ↓ Total CD3+ ↓ CD4+ (Pt1, 2) ↓ CD8+ (Pt1, 2) ↑ Memory (Pt1, 3) | NL Proliferation after anti-CD3 | NR | ↑ B (Pt1) NL for others Pts | ↓ IgG (Pt1) ↓ IgA (Pt1) ↓ IgM (Pt1) | No overt immunodeficiency, but low TRECs (Pt1) Only autoimmunity (Pt2) Autoimmunity (Pt3) | NR (Pt1) Autoimmune hypothyroidism, alopecia areata, anti-thyroglobulin antibodies (Pt2) NR (Pt3) Rheumatoid factor high (Pt4) NR (Pt5) Immune thrombocytopenic purpura (Pt6) | CMV (Pt6) | Briones et al., 2024 |
| − | CD3Z | Homozygous: p.Q70X No transmembrane or intracellular domains | Truncated-mosaicism, 10% of cells revertant in other allele | ↓ Total CD3+ ↓ CD4+ ↓ CD8+ | ↓ Proliferation after PHA, anti-CD3, or tetanus | NR | NL | ↑ Total, IgG, A, M, E ↓ Tetanus, diphtheria, polio response | SCID | Autoantibodies against erythrocytes and neutrophils detected | Pseudomonas aeruginosa, Herpes simplex virus, C. albicans, Streptococcus pneumoniae | Rieux-Laucat et al., 2006 |
| − | CD3Z | Homozygous: p.M1T No extracellular domain | Truncate-0.2% of T cells had revertant somatic mosaicism (p.Q70L/W/Y somatic variants) | ↓ Total CD3+ ↓ CD4+ ↓ CD8+ ↓ Naive ↓ γδT ↑ DN (CD4−CD8) | ↓ Proliferation (short-term) after anti-CD3 antibody ↓ CD69 upregulation ↓ ZAP-70 ↓ ERK phosphorylation | Reduced TCRβ clonality | ↓ Total B ↓ Naive ↑ Memory ↑ DN (CD27−IgD−) | ↑ IgG | SCID, extremely low surface TCR levels | NR | CMV | Marin et al., 2017; Vales-Gomez et al., 2016; Blazquez-Moreno et al., 2017; Briones et al., 2025 |
| − − | ZAP70 | Heterozygous: Kinase domain 3 aa (LEQ) insertion (Pt1) Heterozygous, compound: p.S518R (Pt2) Affects kinase domain | Null | NL Total CD3+ NL CD4+ ↓ CD8+ ↓ Treg | ↓ Proliferation (short-term) after PHA or anti-CD3 ↓ ZAP-70 ↓ ERK phosphorylation ↓ Ca2+ flux | NR | NL | NL or increased total Ig Impaired tetanus antibody levels | SCID-like disease | NR | Upper respiratory infections, CMV (Pt1) CMV, rotavirus (Pt2) Otitis media with perforation, Pneumocystis carinii pneumonia (Pt3) Oral ulcerations, P. carinii pneumonia (Pt4) | Chan et al., 1994; Monafo et al., 1992 |
| − | ZAP70 | Homozygous: p.3 aa (LEQ) insertion in kinase domain | Null | NL Total CD3+ NL CD4+ ↓ CD8+ ↓ Treg | ↓ Proliferation after PHA or anti-CD3 ↓ PLCγ phosphorylation ↓ Ca2+ flux | NR | NL | NL | CID | NR | P. carinii pneumonia CMV retinitis Parainfluenza virus Chronic viral enteritis | Arpaia et al., 1994; Poliani et al., 2013; Roifman et al., 1989 |
| − − | ZAP70 | Homozygous: c.13-bp deletion (nucleotides 1,719–1,731) p.Expected to cause a translational frameshift after amino acid 503; kinase dead | Null | ↑ Total CD3+ ↑ CD4+ ↓ CD8+ | Unresponsive to PHA and anti-CD3 | NR | NL | NL | SCID-like disease | NR | NR | Elder et al., 1994 |
| − −/− | ZAP70 | Homozygous: p.Ala507Val (Pt1) Homozygous: p.Leu337Arg (Pt2) Homozygous: p.Cys564Arg (Pt3) | Null (Pt1, 2) Reduced expression (Pt3) | NL Total CD3+ ↑ or NL CD4+ ↓ CD8+ (Pt1–3) | ↓ Proliferation after PHA | NR | NL | ↓ IgG (Pt1) ↓ IgA (Pt1) ↓ IgM (Pt1) ↓ IgE (Pt1) | SCID (Pt1): Classic symptoms Failure to thrive (Pt2): Wheezing, recurrent gastroenteritis Omenn-like syndrome (Pt3): Eczematous skin lesions, atopic dermatitis with eosinophilia, elevated IgE | NR (Pt1, 2) Omenn-like syndrome with widespread exfoliative dermatitis and subcutaneous nodules (Pt3) | Lower respiratory tract infections, Pneumocystis jirovecii, CMV, Mycoplasma pneumoniae, Mycobacterium (Pt1) Lower respiratory tract infections, and oral thrush (Pt2) Recurrent pneumonia and oral thrush (Pt3) | Turul et al., 2009 |
| − | ZAP70 | Homozygous: p.Pro502ArgfsX43 (Pt1) Homozygous: p.Leu337Arg (Pt2) Homozygous: p.IIe398Ser (Pt3) | Null/kinase dead (Pt1) Expression NA (Pt2) | NL Total CD3+ ↑ or NL CD4+ ↓ CD8+ (Pt1–3) | NR | NR | NL | NL Total Ig | CID: Chronic diarrhea and infections (Pt1) Edema around the eyes and in the lower extremities, infections (Pt2) | NR (Pt1) Coombs-positive hemolytic anemia (Pt2) | Mycobacterium tuberculosis, Campylobacter spp., recurrent oral thrush, encephalomalacias (Pt1) CMV (Pt2) | Akar et al., 2015 |
| − | ZAP70 | Variable (n = 49) | Variable | ↓ CD8+ (97.9%) ↓ CD4+ (12%) | ↓ Proliferation after PHA (95% of cases) | NR | ↓ B (11% of cases) | Defective antibody production (57%) | 73% SCID, 15% CID, 9% ZAP70-deficient phenotype, 3% EBV lymphoproliferative disease | Autoimmunity (19.4% of cases) | Recurrent respiratory infections (81.8% of cases) | Sharifinejad et al., 2020 |
| −/+ | ZAP70 | Homozygous: p.R170C (Pt1) Heterozygous, compound: p.R170C + c.13bp deletion in kinase domain Homozygous: p.R192W (Pt3, 4) | Catalytically inactive (Pt1) Reduced kinase activity (Pt2) SH2 interaction impaired (Pt3, 4) | ↓ Total CD3+ (Pt1, 3) ↓ CD4+ (Pt3) ↓ CD8+ (Pt1–4) | ↓ Proliferation after PHA or anti-CD3 ↓ PLCγ phosphorylation ↓ ERK phosphorylation | NR | NL (Pt1, 2, 4) ↓ B (Pt3) | ↓ IgG (Pt1, 3, 4) ↓ IgA (Pt3, 4) ↓ IgM (Pt3, 4) No titers to diphtheria, tetanus, and pneumococcal vaccine (Pt3) | CID | Alopecia areata and papules (Pt1) Maculopapular rash on face/extremities with unusual clustering, palatal ulcers, bilateral hand arthritis, with inflammation at the proximal, intermediate and distal interphalangeal joints (Pt3) | Pneumocystis pneumonia, mycobacterial infection (Pt1) P. jirovecii pneumonia mycobacterial infections, recurrent respiratory and gastrointestinal infections (Pt2) Pneumonitis and hepatitis due to MMR vaccine (Pt3) | Mongellaz et al., 2023 |
| + | ZAP70 | Compound: p.R192W/R360P | Reduced binding to phosphorylated ζ-chain (R192W) Hyperactive kinase (GOF) disrupted autoinhibitory mechanism (R360P) | ↓ Total CD3+ (Pt1) ↓ CD4+ T (Pt1) ↓ CD8+ T (Pt1, 2) ↓ Naive (Pt2) ↑ Memory (Pt2) | ↓ Proliferation after PHA | NR | ↓ B (Pt1) NL (Pt2) | ↓ IgM (Pt1, 2) ↓ Pneumococcal IgG, Type 3, 8, 12 | Early onset, severe autoimmunity | Nephrotic syndrome, hemarthrosis, inflammatory colitis, bullous pemphigoid, colitis, and proteinuria (Pt1) Bullous pemphigoid, inflammatory colitis, proteinuria (Pt2) | No infection history | Chan et al., 2016 |
| + + | ZAP70 | Homozygous: c.836 + 121G>A (intronic) | Reduced expression of alternatively spliced cDNA No protein data shown | ↓ Total CD3+ ↓ CD4+ T ↓ CD8+ T ↑ Memory T | ↓ Proliferation after PHA or anti-CD3/CD28 ↓ LAT ↓ PLCγ ↓ Akt phosphorylation ↓ Ca2+ flux | NR | NL B ↑ Memory B | NL Total Ig ↑ IgE (Pt1) ↓ Anti-poliovirus, anti-tetanus | Healthy: T cells functionally impaired | NR | No serious infection history | Picard et al., 2009 |
| − − | LAT | Homozygous: p.Leu16AlafsX28 | Expression null | ↓ Total CD3+ (Pt1) ↓ CD4+ T (Pt1–3) ↓ CD8+ T (Pt1–3) | ↓ Proliferation after PHA ↓ CD69 upregulation ↓ Vav ↓ SLP-76/LAT phosphorylation ↓ Ca2+ mobilzation | NR | NL | IgG was present (likely maternal transfer) (Pt2, 3, 5) IgA (below level of detection) (Pt2, 3, 5) ↓↓ IgM (Pt2, 3, 5) | SCID (T−B+NK+): Severe recurrent infections and failure to thrive | NR | Recurrent infections | Bacchelli et al., 2017 |
| − | LAT | Homozygous: p.Y207fsTer33 | Truncate | ↓ Total CD3+ ↓ CD4+ T ↓ CD8+ T | ↓ Proliferation after PHA | NR | NL | NL | Leaky SCID (T−B+NK+): Fever, BCGosis, axillary and supraclavicular lymphadenopathy, failure to thrive | NR | BCG | Alizadeh et al., 2023 |
| −/+ | LAT | Homozygous: c.268_269delGG exon 5 premature stop | Truncate Contains an intact extracellular and transmembrane region but a shortened intracellular region, eliminating the known major phosphorylation sites Y132, Y171, Y191, and Y226 | ↓ Total CD3+ (Pt1) ↓ CD4+ T (Pt1–3) NL CD8+ T ↓ Naive (Pt2) ↑ Memory (Pt2) ↑ γδT (Pt2, 3) ↓ Treg (Pt2) | ↓ Proliferation NL ZAP70, ITK phosphorylation Absent PLCγ1 phosphorylation ↓ ERK phosphorylation ↓ CD69 | NR | NL (Pt2) ↓ B (Pt1, 3) | Progressive hypogammaglobulinemia (Pt1, 2) Hypergammagloblunemia (Pt3) Hepatitis B−, measles−, mumps−, rubella− (Pt1) Rubella+, measles−, EBV+, CMV− (Pt3) | CID: Lymphoproliferation, and life-threatening autoimmune disease since early infancy | Coombs+ AIHA, ITP, autoimmune neutropenia (Pt1) Coombs+ AIHA, ITP (Pt2) Anti-ADAMTS13+ microangiopathic hemolytic anemia (Pt3) | Recurrent pneumonia, EBV/CMV viremia, CMV pneumonia (Pt1) Congenital toxoplasmosis, recurrent pneumonia, VZV, CMV viremia, Candida pneumonia with adenovirus (Pt2) Recurrent pneumonia, urinary infections, gastroenteritis, CMV viremia (Pt3) | Keller et al., 2016 |
| − | SLP76 | Homozygous: c.957 + 1G>A p.K309FSx17 | Expression null (in vivo) or Truncate (in Jurkat) | ↓ Total CD3+ (Pt1) ↓ CD4+ T (Pt1–3) ↑ CD8+ T ↓ Naive (Pt2) ↑ Memory ↑ γδT (Pt2, 3) NL Treg | ↓ Proliferation after PHA or anti-CD3/CD28 Cytokine defect upon TCR activation ↓ CD69, CD25, and CD98 upregulation ↓ PLCγ and ERK activation | Restricted TRG and TRB repertoire | ↓ Class switched memory B (IgM−IgD−CD19+CD27+) ↓ Transitional B (IgM2+ CD19+CD382+) ↑ Naive (IgD+CD27−CD19+) ↑ Immature B (IgD+CD38+CD19+ | Pre-IVIG data not available | CID: Early-onset life-threatening infections, T and B cell immunodeficiency, severe neutrophil function defect, impaired platelet aggregation, recurrent skin abscesses, skin rash | Coombs-positive hemolytic anemia | Aspergillus fumigatus, BCG, CMV | Lev et al., 2021 |
| − | SLP76 | Homozygous: c.991del.C p. Q331Sfs*6 | Truncate (in Jurkat) | ↓ Total CD3+ ↓ CD4+ T ↓ CD8+ T | ↓ Proliferation after PHA or anti-CD3/CD28 Cytokine defect upon TCR activation ↓ CD69 upregulation ↓ ERK activation ↓ Ca2+ flux | Skewed/restricted TCR-Vβ | NL | Pre-IVIG data not available | CID with EBV-related lymphoma | Pancytopenia, lymphoproliferation, thrombocytopenia | Enterovirus, PJP, EBV | Lev et al., 2023 |
| −−/+ | SLP76 | Compound: p.P190R + p.R204W | Reduced in B, CD4+, CD8+ T, and NK cells | All NL ↓ TemRO | ↓ S6 and PLCγ1 phosphorylation | NR | ↓ Unswitched memory B ↓ Class-switched memory B | ↓ Serum IgA Poor response to Prevenar13 and Pneumovax23 | CID: Early-onset immune dysregulation | Specific antibody deficiency, autoimmunity, and inflammatory bowel disease, autoimmune hemolytic anemia | Recurrent oral mucocutaneous candidiasis Recurrent chest infections: Morganella morganii, Raoultella planticola, Enterobacter cloacae complex, Staphylococcus aureus, P. aeruginosa, C. albicans, Serratia marcescens, Klebsiella oxytoca, and Citrobacter koseri, Stenotrophomonas sp., C. albicans, methicillin-resistant S. aureus, and Pseudomonas sp. | Edwards et al., 2023 |
| −/+ | ITK | Homozygous: p.R335W SH2 domain mutation | Expression null (in Jurkat) | ↓ Total CD3+ ↓ CD4+ T ↓ CD8+ T ↓ Treg ↓ NKT | NL PHA response ↓ Proliferation after anti-CD3/CD28 ↓ Ca2+ flux | NR | ↑ B | Hypogammaglobulinemia NL vaccine response (diphtheria, tetanus, strep, and Hib) | CID with EBV-associated lymphoproliferative disorder and immune dysregulation | Anemia, thrombocytopenia (Pt1) | Aphthous stomatitis, candida stomatitis, EBV, BK polyomavirus infection, P. jirovecii pneumonia (Pt1) EBV (Pt2) | Huck et al., 2009 |
| −/+ | ITK | Homozygous: p.Thr110ArgfsTer155 | Nonsense mediated decay (no protein data shown) | ↓ Total CD3+ ↓ Th17 ↑ Th1 ↑ Treg | ↓ Proliferation after anti-CD3/CD28 | NR | ↑ B | NR | Hodgkin’s lymphoma | NR | EBV, pneumonia | Eken et al., 2019 |
| −/+ | ITK | Homozygous: p.Y588X Predicted to produce kinase dead truncate | Undetectable protein | ↓ Total CD3+ ↓ CD4+ T (Pt2) ↑ CD8+ T (Pt2) ↓ CD8+ T (Pt3) ↓ Naive (Pt2) ↑ Memory (Pt2) ↓ Treg ↓ NKT (Pt3) | ↓ Ca2+ flux | NR | ↑ B | Hypogammaglobulinemia | Hodgkin’s lymphoma | Glomerulonephritis, Tubulointerstitial nephritis (Pt2) | Persistent infectious mononucleosis, including recurrent febrile episodes, lymphadenopathies, extremely high EBV viral load | Stepensky et al., 2011 |
| + | ITK | p.R29H (Pt1) p.D500T, F501L, M503X (Pt2) | Reduced membrane targeting (Pt1) Reduced protein (Pt2) | ↓ Total CD3+ ↓ CD4+ T (Pt1, 2) ↓ CD8+ T ↓ Naive (Pt1, 2) ↑ Memory (Pt2) ↓ NKT (Pt1, 2) | ↓ Ca2+ flux | NR | ↑ B | Hypogammaglobulinemia (Pt1) | B cell lymphoma Proliferative disease (Pt1) Large B cell lymphoma (Pt2): Lymphomatoid granulomatosis | AIHA, ITP (Pt1) | EBV | Linka et al., 2012 |
| TCR SS . | Gene . | Mutation . | Protein . | T cells . | B cells . | Clinical presentation . | Autoimmunity . | Infection . | Citation . | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Relative numbers . | Responsiveness . | Repertoire . | Relative numbers . | Antibodies . | ||||||||
| – – | TCRA | Homozygous p.Ser116* | Null or truncate | ↓ Total CD3+ ↓ CD4+ T ↓ CD8+ T ↓ Naive ↑ CD45RO+ | ↓ Proliferation after PHA | Abnormal Vβ | NL | NR | SCID-like disease | NR | NR | Garkaby et al., 2022 |
| – – | TCRA | Homozygous: p.Trp65* (Pt1) Homozygous: p.Arg121* (Pt2) | Null or complete LOF | ↓ Total CD3+ ↓ CD4+ TCRαβ ↓ CD8+ TCRαβ ↓ Naive ↑ γδT | None (TCR complex does not form) | Mostly γδT, few αβ, limited TRAV | NL | ↑ IgG (Pt1) ↑ IgA (Pt1, 2, 3) ↔ IgM (Pt1, 2, 3) ↑ IgE (Pt1, 2, 3) | SCID | NR | CMV (Pt1) BCG (Pt1, 2) Salmonella and oral thrush (Pt2) | Materna et al., 2025 |
| −/+ | TCRA | Homozygous: p.Thr107LeufsX56 | Partial deficiency | ↓ CD4+ TCRαβ ↓ CD8+ TCRαβ ↓ Naive ↑ γδT | ↓ Proliferation after PHA, anti-CD3, or PWM (mislocalized TCR) | Mostly γδT, few αβ | NL | NL (total Ig subtypes) NL (tetanus, pneumo, and Hib) ↑ IgE-Pt1 | CID: Recurrent respiratory tract infections, otitis media, candidiasis, diarrhea, and failure to thrive | Hypereosinophilia, low-titer antinuclear antibodies (ANA), vitiligo, and alopecia areata (Pt1) Hypereosinophilia, eczema, autoimmune hemolytic anemia, anti-lymphocyte antibodies, anti-TTG antibodies, low-titer ANA, and pityriasis rubra pilaris (Pt2) | Cryptosporidium Staphylococcus aureus Streptococcus pneumoniae Pseudomonas Rotavirus Salmonella enterica Varicella zoster | Morgan et al., 2011 |
| −/+ | TCRA | Homozygous: p.Thr107LeufsX56 | Partial deficiency | ↓ Total CD3+ ↓ CD4+ TCRαβ ↓ CD8+ TCRαβ ↓ Naive ↑ γδT | NR Mislocalized TCR | Mostly γδT, few αβ, and limited TRAV | ↓ B | ↑ IgG (Pt1) ↑ IgA (Pt1–3) ↔ IgM (Pt1–3) ↑ IgE (Pt1–3) | CID: Recurrent lower respiratory tract infections, lymphoproliferation, warts, and mimics DOCK8 deficiency | No autoimmunity | Lower respiratory tract infections and EBV (Pt3) | Rawat et al., 2021 |
| – – | CD3D | Homozygous: p.R68X | Null or complete LOF | ↓ Total CD3+ ↓ CD4+ TCRαβ ↓ CD8+ TCRαβ ↓ Naive ↑ γδT | ↓ Proliferation after PHA | NR | NL | NL Total Ig | SCID: Fever, tachypnea, tachycardia, respiratory arrest, chronic diarrhea, respiratory distress, lethargy, and jaundice | NR | Adenovirus (Pt2) CMV (Pt3) | Dadi et al., 2003 |
| – – | CD3D | Homozygous: p.Trp43* (with BTK LOF mutation) | Null | ↓ Total CD3+ ↓ CD4+ T ↓ CD8+ T | NR | NR | NL | Hypogammagloblunemia due to concurrent BTK mutation | SCID | NR | Rotavirus BCGosis due to vaccination Oral thrush (Pt2) | Al-Hammadi et al., 2020 |
| – – | CD3D | Homozygous: p.C93X (Pt1) Homozygous: p.R68X (Pt2) | Truncate | ↓ Total CD3+ ↓ CD4+ T ↓ CD8+ T | NR (Pt1) ↓ Proliferation (Pt2) | NR | NL | NR | SCID (T−B+NK+) | NR | NR | de Saint Basile et al., 2004 |
| – – | CD3D | Homozygous: c.56-1G>T Exon 1 skipping | Truncate | ↓ Total CD3+ ↓ CD4+ T ↓ CD8+ T | NR | NR | NL | ↓ IgG ↓ IgA ↓ IgM | SCID: Failure to thrive | NR | Recurrent sinopulmonary infections and candidiasis, BCG lymphadenitis | Sonmez et al., 2025 |
| – – | CD3D | Homozygous: p.S53X (Pt1) Homozygous: c.IVS2-2A>G (Pt2) | Truncate or null (Pt1) Truncate (Pt2) | ↓ Total CD3+ ↓ CD4+ TCRαβ ↓ CD8+ TCRαβ ↓ Naive ↑ γδT | NR | NR | NL (Pt1) ↑ B (Pt2) | ↓ IgG (Pt1) ↓ IgA (Pt1) ↑ IgE (Pt2) | SCID: Failure to thrive | NR (Pt1) Eczema (Pt2) Omen syndrome (Pt2) | Recurrent pneumonia Septicemia Candida (Pt2) | Vignesh et al., 2021 |
| – – | CD3D | Homozygous: c.IVS2-2A>G mRNA lacks exon3 | Truncate | ↓ Total CD3+ | NR | NR | NL (Pt1) ↑ B (Pt2) | ↓ IgG (Pt1) ↓ IgA (Pt1) ↑ IgE (Pt2) | SCID | NR | CMV, pneumonitis (Pt1); oral thrush (Pt2) | Takada et al., 2005 |
| – | CD3D | Homozygous: c.IVS2+5G>A G>A at position +5 in the 5′ splice donor site of intron 2 (in frame exon 2 deletion) | Truncate | ↓ Total CD3+ ↓ CD4+ TCRαβ ↓ CD8+ TCRαβ ↓ Naive ↑ γδT | ↓ CD25/CD69 upregulation upon activation | NR | NL | ↔ IgG ↔ IgA ↑ IgE (Pt1) Antibody response to protein antigens impaired (Pt1) Hypogammagloblunemia (Pt2) | Leaky SCID: Failure to thrive, severe diarrhea, prostrating diarrhea, respiratory distress, discrete lymphopenia, severe hypogammaglobulinemia, and protein-losing enteropathy | Hyper-IgE Eosinophilia Atopic dermatitis (all Pt1) | Pt1: Bronchopneumonia Salmonella, Campylobacter, Cryptosporidium, oral candidiasis (Pt1) Urine CMV, nasal adenovirus (Pt2) | Gil et al., 2011 |
| – | CD3G | Homozygous: c.80-1G>C Splice-acceptor variant causing aberrant splicing with a 17-bp exonic deletion and frameshift (IVS2-1G>C) | Null | ↓ CD3 T NL CD4+ T ↓ CD8+ T ↓ Naive T ↑ Memory T | NR | NR | NR | Selective Ig2 deficiency (Pt1) NL Antibody responses to protein antigens | SCID (with features of autoimmunity): Failure to thrive, intractable diarrhea, autoimmune hemolytic anemia, mild respiratory distress, asthma | Serum autoantibodies against mitochondria, smooth muscle, and intestinal epithelial cells Severe autoimmune hemolytic anemia and respiratory distress Autoimmune enteropathy with gut epithelial cell autoantibodies (Pt1) Asthma, vitiligo, and atopic eczema (Pt2) | Repeated gram-positive and negative bacterial infections, viral pneumonia, parainfluenza 3 (Pt1), Hecht’s pneumonia (Pt2) | Arnaiz-Villena et al., 1992; Allende et al., 2000 |
| −/+ | CD3G | Homozygous: c.1A > G p.translation start change | Null or complete LOF | NL Total CD3+ ↓ CD4+ TCRαβ ↓ Naive ↑ Memory T ↓ Treg | ↓ Proliferation after PHA, Con-A, or anti-CD3 | Reduced diversity | ↓ All memory B | Hypogammaglobulinemia Impaired vaccination response to Haemophilus influenzae type B and Pneumococcus | CID with autoimmunity | GLILD Autoimmune enteropathy AIHA | EBV Clostridioides difficile Klebsiella pneumoniae | Delmonte et al., 2021 |
| + | CD3G | Homozygous: c.del213A p.Asn71Metfs*110 | Null or complete LOF | NR Treg NL | NL Proliferation after PHA | NR | ↓ Switched memory B ↓ CD40L | Hypogammaglobulinemia ↓ IgG ↓ IgA ↓ IgM ↓ IgE | CVID: Without recognizable autoimmunity | NR | Recurrent sinopulmonary infections without opportunistic infections | Lee et al., 2019 |
| − | CD3G | Homozygous: p.K69X | Complete LOF | Mild αβ and γδ T lymphocytopenia | ↓ Proliferation after PHA or antigens (low CD3 expression) | NR | NL | NL | SCID: Chronic diarrhea (Pt1, 2) | Psoriasis, low titer microsomal and thyroglobulin autoantibodies (Pt3) | Pulmonary infections, recurrent otitis media, oral thrush, severe diaper dermatitis, and perianal fistula (Pt1) Oral thrush, perianal fistula (Pt2) | Recio et al., 2007 |
| + | CD3G | Homozygous: p.K69X | Truncate | ↓ Total CD3+ ↓ CD4+ | NR low CD3 expression | NR | NL | NL Ig ↓ IgA | CID with autoimmunity | Psoriasis Asthma | Upper/lower respiratory tract infections VZV infection | Sonmez et al., 2025 |
| + | CD3G | Homozygous: p.Lys71fs | Truncate | ↓ Total CD3+ NL CD4+ ↓ CD8+ ↓ Naive ↑ Memory ↓ Treg | NR | NR | ↑ Naive B ↑ Memory B | Positive ANA, high IgE | Lupus-like disease: With immunodeficiency | Autoimmune thyroiditis AIHA ITP Asthma | Recurrent respiratory infections, sinusitis, and latent tuberculosis infection | Lin et al., 2024 |
| + + | CD3G | Homozygous: c.80-1G>C | Splice variant-reduced expression | ↓ Total CD3+ ↓ CD4+ ↓ CD8+ ↓ Naive (except Pt1) ↓ γδT | NR | NR | NL | ↑ IgG (Pt1, 4) ↓ IgA (Pt3, 4) ↓ IgM (Pt4) ↑ IgE (Pt1, 2) Low anti-HBs titer (Pt4) | CID (T−B+NK+) | Diffuse vitiligo (Pt1) Autoimmune thyroiditis (Pt1–5) Atopic dermatitis/pityriasis alba (Pt2) Autoimmune hepatitis (Pt4) Autoimmune hemolytic anemia (Pt4, 5) Immune thrombocytopenic purpura (Pt4) | Recurrent upper and lower respiratory tract infections VZV Candida albicans Giardia intestinalis | Gokturk et al., 2014; Tokgoz et al., 2013 |
| + + | CD3G | Homozygous: c.1A>G (Pt1) Homozygous: c.80-1G>C (Pt2–5) Compound: c.1A>G /c.80-1G>C (Pt6) | Reduced surface expression | NL (Pt1, 4, 5, 6) ↓ Total CD3+ (Pt2, 3) NL CD4+ NL CD8+ ↑ Memory ↑ TEMRA ↑ Exhausted CD8+ ↓ Treg | ↓ Proliferation after PHA ↓ CD25 after anti-CD3/28 | Skewed use of TRBV and TRBJ | NR | NL for most ↓ IgG (Pt4) ↓ IgA (Pt4) | Immunodeficiency with autoimmunity | Autoimmune enteropathy, GLILD, AIHA (Pt1) Hypothyroidism (Pt2, 3, 4, 6) AIHA, ITP, nephropathy, ALPS (Pt4) Thyroiditis (Pt5) Vitiligo (Pt6) | Klebsiella pneumoniae, MSSA, severe EBV (Pt1) Acute bronchitis (Pt2) RRTI, bronchiectasis (Pt4) Soft tissue abscesses, viral meningitis (Pt6) | Rowe et al., 2018 |
| − − | CD3E | c.fs43 Creates stop 13 residues downstream p.extracellular domain only | Null | ↓ Total CD3+ ↓ CD4+ ↓ CD8+ | NR | NR | NL | ↓ IgA (Pt2) ↓ IgM (Pt2) | SCID | NR | Pneumonitis, oral candidiasis, disseminated CMV infection | de Saint Basile et al., 2004 |
| − − | CD3E | NR | Null | ↓ Total CD3+ ↓ CD4+ | Absence of T cell proliferation, following PHA anti-CD3 and anti-CD2 antibody-triggered T cell activation | NR | NR | NR | SCID | NR | Recurrent lung infections | Thoenes et al., 1990; Thoenes et al., 1992 |
| − − | CD3E | Homozygous: p.Y96X (Pt1) Homozygous: c.352 + 1G>A (Pt2) | Truncate (Pt1) Splice variant (Pt2) | ↓ Total CD3+ (Pt1) | NR | NR | ↑ B | ↓ IgG (Pt1, 2) ↓ IgA (Pt1, 2) ↓ IgM (Pt1) | SCID: Persistent diarrhea | NR | Recurrent pneumonia Disseminated BCGosis (Pt1) Tuberculosis and Pseudomonas (Pt2) | Vignesh et al., 2021 |
| − − | CD3E | Homozygous: c.fs*9 p.L58H | Truncate | ↓ Total CD3+ ↓ CD4+ ↓ CD8+ ↓ Treg | NR | NR | ↑ B | ↓ IgG (Pt1, 2) ↓ IgA (Pt1, 2) ↓ IgM (Pt1) | SCID (T−B+NK+): ARDS, diarrhea | NR | Sepsis CMV (Pt1) Pneumonitis, oral candidiasis (Pt2) | Firtina et al., 2017 |
| − − | CD3E | Homozygous: c.567 + 42_567 + 73del | Null-mRNA stability compromised | ↓ Total CD3+ ↓ CD4+ ↓ CD8+ | NR | NR | NL | ↓ IgG (Pt1) ↓ IgA (Pt1, 2) ↓ IgM (Pt1) | SCID: Fever | NR (Pt1) Autoimmune hepatitis (Pt2) | Oral candidiasis, lung infection (Pt1) Persistent candidiasis, CMV, pneumonia (Pt2) | Sonmez et al., 2025 |
| − | CD3E | Homozygous: c.IVS7DS, T-C, +2 p.W59X | Truncate-reduced expression | ↓ Total CD3+ ↓ CD4+ ↓ CD8+ | Absence of T cell proliferation, CD25 expression, and calcium flux after anti-CD3 and anti-CD2 | NR | NL | NL Total IgA Defective poliovirus or isohemagglutinin IgA | CID: Recurrent pneumonia | NR | Hemophilus influenzae Recurrent otitis media | Soudais et al., 1993; Le Deist et al., 1991 |
| −− | CD3Z | Homozygous: p.D138fsX272 eliminates ITAM3 | Null | ↓ Total CD3+ ↓ CD4+ ↓ CD8+ | ↓ Proliferation after PHA, Con A, PWM, Candida, anti-CD3ε, autologous cells, or allogeneic cells | Oligoclonal | NL | Pre-IVIG values not available | SCID (T−B+NK+): Failure to thrive, chronic cough, chronic mild rash, gastroenteritis | No definitive autoimmunity, but some symptoms | CMV Salmonella gastroenteritis Recurrent otitis media | Roberts et al., 2007 |
| + + | CD3Z | Heterozygous: p.Y152X and p.Q101X ITAM3 eliminated | Dominant negative | ↓ Total CD3+ ↓ CD4+ (Pt1, 2) ↓ CD8+ (Pt1, 2) ↑ Memory (Pt1, 3) | NL Proliferation after anti-CD3 | NR | ↑ B (Pt1) NL for others Pts | ↓ IgG (Pt1) ↓ IgA (Pt1) ↓ IgM (Pt1) | No overt immunodeficiency, but low TRECs (Pt1) Only autoimmunity (Pt2) Autoimmunity (Pt3) | NR (Pt1) Autoimmune hypothyroidism, alopecia areata, anti-thyroglobulin antibodies (Pt2) NR (Pt3) Rheumatoid factor high (Pt4) NR (Pt5) Immune thrombocytopenic purpura (Pt6) | CMV (Pt6) | Briones et al., 2024 |
| − | CD3Z | Homozygous: p.Q70X No transmembrane or intracellular domains | Truncated-mosaicism, 10% of cells revertant in other allele | ↓ Total CD3+ ↓ CD4+ ↓ CD8+ | ↓ Proliferation after PHA, anti-CD3, or tetanus | NR | NL | ↑ Total, IgG, A, M, E ↓ Tetanus, diphtheria, polio response | SCID | Autoantibodies against erythrocytes and neutrophils detected | Pseudomonas aeruginosa, Herpes simplex virus, C. albicans, Streptococcus pneumoniae | Rieux-Laucat et al., 2006 |
| − | CD3Z | Homozygous: p.M1T No extracellular domain | Truncate-0.2% of T cells had revertant somatic mosaicism (p.Q70L/W/Y somatic variants) | ↓ Total CD3+ ↓ CD4+ ↓ CD8+ ↓ Naive ↓ γδT ↑ DN (CD4−CD8) | ↓ Proliferation (short-term) after anti-CD3 antibody ↓ CD69 upregulation ↓ ZAP-70 ↓ ERK phosphorylation | Reduced TCRβ clonality | ↓ Total B ↓ Naive ↑ Memory ↑ DN (CD27−IgD−) | ↑ IgG | SCID, extremely low surface TCR levels | NR | CMV | Marin et al., 2017; Vales-Gomez et al., 2016; Blazquez-Moreno et al., 2017; Briones et al., 2025 |
| − − | ZAP70 | Heterozygous: Kinase domain 3 aa (LEQ) insertion (Pt1) Heterozygous, compound: p.S518R (Pt2) Affects kinase domain | Null | NL Total CD3+ NL CD4+ ↓ CD8+ ↓ Treg | ↓ Proliferation (short-term) after PHA or anti-CD3 ↓ ZAP-70 ↓ ERK phosphorylation ↓ Ca2+ flux | NR | NL | NL or increased total Ig Impaired tetanus antibody levels | SCID-like disease | NR | Upper respiratory infections, CMV (Pt1) CMV, rotavirus (Pt2) Otitis media with perforation, Pneumocystis carinii pneumonia (Pt3) Oral ulcerations, P. carinii pneumonia (Pt4) | Chan et al., 1994; Monafo et al., 1992 |
| − | ZAP70 | Homozygous: p.3 aa (LEQ) insertion in kinase domain | Null | NL Total CD3+ NL CD4+ ↓ CD8+ ↓ Treg | ↓ Proliferation after PHA or anti-CD3 ↓ PLCγ phosphorylation ↓ Ca2+ flux | NR | NL | NL | CID | NR | P. carinii pneumonia CMV retinitis Parainfluenza virus Chronic viral enteritis | Arpaia et al., 1994; Poliani et al., 2013; Roifman et al., 1989 |
| − − | ZAP70 | Homozygous: c.13-bp deletion (nucleotides 1,719–1,731) p.Expected to cause a translational frameshift after amino acid 503; kinase dead | Null | ↑ Total CD3+ ↑ CD4+ ↓ CD8+ | Unresponsive to PHA and anti-CD3 | NR | NL | NL | SCID-like disease | NR | NR | Elder et al., 1994 |
| − −/− | ZAP70 | Homozygous: p.Ala507Val (Pt1) Homozygous: p.Leu337Arg (Pt2) Homozygous: p.Cys564Arg (Pt3) | Null (Pt1, 2) Reduced expression (Pt3) | NL Total CD3+ ↑ or NL CD4+ ↓ CD8+ (Pt1–3) | ↓ Proliferation after PHA | NR | NL | ↓ IgG (Pt1) ↓ IgA (Pt1) ↓ IgM (Pt1) ↓ IgE (Pt1) | SCID (Pt1): Classic symptoms Failure to thrive (Pt2): Wheezing, recurrent gastroenteritis Omenn-like syndrome (Pt3): Eczematous skin lesions, atopic dermatitis with eosinophilia, elevated IgE | NR (Pt1, 2) Omenn-like syndrome with widespread exfoliative dermatitis and subcutaneous nodules (Pt3) | Lower respiratory tract infections, Pneumocystis jirovecii, CMV, Mycoplasma pneumoniae, Mycobacterium (Pt1) Lower respiratory tract infections, and oral thrush (Pt2) Recurrent pneumonia and oral thrush (Pt3) | Turul et al., 2009 |
| − | ZAP70 | Homozygous: p.Pro502ArgfsX43 (Pt1) Homozygous: p.Leu337Arg (Pt2) Homozygous: p.IIe398Ser (Pt3) | Null/kinase dead (Pt1) Expression NA (Pt2) | NL Total CD3+ ↑ or NL CD4+ ↓ CD8+ (Pt1–3) | NR | NR | NL | NL Total Ig | CID: Chronic diarrhea and infections (Pt1) Edema around the eyes and in the lower extremities, infections (Pt2) | NR (Pt1) Coombs-positive hemolytic anemia (Pt2) | Mycobacterium tuberculosis, Campylobacter spp., recurrent oral thrush, encephalomalacias (Pt1) CMV (Pt2) | Akar et al., 2015 |
| − | ZAP70 | Variable (n = 49) | Variable | ↓ CD8+ (97.9%) ↓ CD4+ (12%) | ↓ Proliferation after PHA (95% of cases) | NR | ↓ B (11% of cases) | Defective antibody production (57%) | 73% SCID, 15% CID, 9% ZAP70-deficient phenotype, 3% EBV lymphoproliferative disease | Autoimmunity (19.4% of cases) | Recurrent respiratory infections (81.8% of cases) | Sharifinejad et al., 2020 |
| −/+ | ZAP70 | Homozygous: p.R170C (Pt1) Heterozygous, compound: p.R170C + c.13bp deletion in kinase domain Homozygous: p.R192W (Pt3, 4) | Catalytically inactive (Pt1) Reduced kinase activity (Pt2) SH2 interaction impaired (Pt3, 4) | ↓ Total CD3+ (Pt1, 3) ↓ CD4+ (Pt3) ↓ CD8+ (Pt1–4) | ↓ Proliferation after PHA or anti-CD3 ↓ PLCγ phosphorylation ↓ ERK phosphorylation | NR | NL (Pt1, 2, 4) ↓ B (Pt3) | ↓ IgG (Pt1, 3, 4) ↓ IgA (Pt3, 4) ↓ IgM (Pt3, 4) No titers to diphtheria, tetanus, and pneumococcal vaccine (Pt3) | CID | Alopecia areata and papules (Pt1) Maculopapular rash on face/extremities with unusual clustering, palatal ulcers, bilateral hand arthritis, with inflammation at the proximal, intermediate and distal interphalangeal joints (Pt3) | Pneumocystis pneumonia, mycobacterial infection (Pt1) P. jirovecii pneumonia mycobacterial infections, recurrent respiratory and gastrointestinal infections (Pt2) Pneumonitis and hepatitis due to MMR vaccine (Pt3) | Mongellaz et al., 2023 |
| + | ZAP70 | Compound: p.R192W/R360P | Reduced binding to phosphorylated ζ-chain (R192W) Hyperactive kinase (GOF) disrupted autoinhibitory mechanism (R360P) | ↓ Total CD3+ (Pt1) ↓ CD4+ T (Pt1) ↓ CD8+ T (Pt1, 2) ↓ Naive (Pt2) ↑ Memory (Pt2) | ↓ Proliferation after PHA | NR | ↓ B (Pt1) NL (Pt2) | ↓ IgM (Pt1, 2) ↓ Pneumococcal IgG, Type 3, 8, 12 | Early onset, severe autoimmunity | Nephrotic syndrome, hemarthrosis, inflammatory colitis, bullous pemphigoid, colitis, and proteinuria (Pt1) Bullous pemphigoid, inflammatory colitis, proteinuria (Pt2) | No infection history | Chan et al., 2016 |
| + + | ZAP70 | Homozygous: c.836 + 121G>A (intronic) | Reduced expression of alternatively spliced cDNA No protein data shown | ↓ Total CD3+ ↓ CD4+ T ↓ CD8+ T ↑ Memory T | ↓ Proliferation after PHA or anti-CD3/CD28 ↓ LAT ↓ PLCγ ↓ Akt phosphorylation ↓ Ca2+ flux | NR | NL B ↑ Memory B | NL Total Ig ↑ IgE (Pt1) ↓ Anti-poliovirus, anti-tetanus | Healthy: T cells functionally impaired | NR | No serious infection history | Picard et al., 2009 |
| − − | LAT | Homozygous: p.Leu16AlafsX28 | Expression null | ↓ Total CD3+ (Pt1) ↓ CD4+ T (Pt1–3) ↓ CD8+ T (Pt1–3) | ↓ Proliferation after PHA ↓ CD69 upregulation ↓ Vav ↓ SLP-76/LAT phosphorylation ↓ Ca2+ mobilzation | NR | NL | IgG was present (likely maternal transfer) (Pt2, 3, 5) IgA (below level of detection) (Pt2, 3, 5) ↓↓ IgM (Pt2, 3, 5) | SCID (T−B+NK+): Severe recurrent infections and failure to thrive | NR | Recurrent infections | Bacchelli et al., 2017 |
| − | LAT | Homozygous: p.Y207fsTer33 | Truncate | ↓ Total CD3+ ↓ CD4+ T ↓ CD8+ T | ↓ Proliferation after PHA | NR | NL | NL | Leaky SCID (T−B+NK+): Fever, BCGosis, axillary and supraclavicular lymphadenopathy, failure to thrive | NR | BCG | Alizadeh et al., 2023 |
| −/+ | LAT | Homozygous: c.268_269delGG exon 5 premature stop | Truncate Contains an intact extracellular and transmembrane region but a shortened intracellular region, eliminating the known major phosphorylation sites Y132, Y171, Y191, and Y226 | ↓ Total CD3+ (Pt1) ↓ CD4+ T (Pt1–3) NL CD8+ T ↓ Naive (Pt2) ↑ Memory (Pt2) ↑ γδT (Pt2, 3) ↓ Treg (Pt2) | ↓ Proliferation NL ZAP70, ITK phosphorylation Absent PLCγ1 phosphorylation ↓ ERK phosphorylation ↓ CD69 | NR | NL (Pt2) ↓ B (Pt1, 3) | Progressive hypogammaglobulinemia (Pt1, 2) Hypergammagloblunemia (Pt3) Hepatitis B−, measles−, mumps−, rubella− (Pt1) Rubella+, measles−, EBV+, CMV− (Pt3) | CID: Lymphoproliferation, and life-threatening autoimmune disease since early infancy | Coombs+ AIHA, ITP, autoimmune neutropenia (Pt1) Coombs+ AIHA, ITP (Pt2) Anti-ADAMTS13+ microangiopathic hemolytic anemia (Pt3) | Recurrent pneumonia, EBV/CMV viremia, CMV pneumonia (Pt1) Congenital toxoplasmosis, recurrent pneumonia, VZV, CMV viremia, Candida pneumonia with adenovirus (Pt2) Recurrent pneumonia, urinary infections, gastroenteritis, CMV viremia (Pt3) | Keller et al., 2016 |
| − | SLP76 | Homozygous: c.957 + 1G>A p.K309FSx17 | Expression null (in vivo) or Truncate (in Jurkat) | ↓ Total CD3+ (Pt1) ↓ CD4+ T (Pt1–3) ↑ CD8+ T ↓ Naive (Pt2) ↑ Memory ↑ γδT (Pt2, 3) NL Treg | ↓ Proliferation after PHA or anti-CD3/CD28 Cytokine defect upon TCR activation ↓ CD69, CD25, and CD98 upregulation ↓ PLCγ and ERK activation | Restricted TRG and TRB repertoire | ↓ Class switched memory B (IgM−IgD−CD19+CD27+) ↓ Transitional B (IgM2+ CD19+CD382+) ↑ Naive (IgD+CD27−CD19+) ↑ Immature B (IgD+CD38+CD19+ | Pre-IVIG data not available | CID: Early-onset life-threatening infections, T and B cell immunodeficiency, severe neutrophil function defect, impaired platelet aggregation, recurrent skin abscesses, skin rash | Coombs-positive hemolytic anemia | Aspergillus fumigatus, BCG, CMV | Lev et al., 2021 |
| − | SLP76 | Homozygous: c.991del.C p. Q331Sfs*6 | Truncate (in Jurkat) | ↓ Total CD3+ ↓ CD4+ T ↓ CD8+ T | ↓ Proliferation after PHA or anti-CD3/CD28 Cytokine defect upon TCR activation ↓ CD69 upregulation ↓ ERK activation ↓ Ca2+ flux | Skewed/restricted TCR-Vβ | NL | Pre-IVIG data not available | CID with EBV-related lymphoma | Pancytopenia, lymphoproliferation, thrombocytopenia | Enterovirus, PJP, EBV | Lev et al., 2023 |
| −−/+ | SLP76 | Compound: p.P190R + p.R204W | Reduced in B, CD4+, CD8+ T, and NK cells | All NL ↓ TemRO | ↓ S6 and PLCγ1 phosphorylation | NR | ↓ Unswitched memory B ↓ Class-switched memory B | ↓ Serum IgA Poor response to Prevenar13 and Pneumovax23 | CID: Early-onset immune dysregulation | Specific antibody deficiency, autoimmunity, and inflammatory bowel disease, autoimmune hemolytic anemia | Recurrent oral mucocutaneous candidiasis Recurrent chest infections: Morganella morganii, Raoultella planticola, Enterobacter cloacae complex, Staphylococcus aureus, P. aeruginosa, C. albicans, Serratia marcescens, Klebsiella oxytoca, and Citrobacter koseri, Stenotrophomonas sp., C. albicans, methicillin-resistant S. aureus, and Pseudomonas sp. | Edwards et al., 2023 |
| −/+ | ITK | Homozygous: p.R335W SH2 domain mutation | Expression null (in Jurkat) | ↓ Total CD3+ ↓ CD4+ T ↓ CD8+ T ↓ Treg ↓ NKT | NL PHA response ↓ Proliferation after anti-CD3/CD28 ↓ Ca2+ flux | NR | ↑ B | Hypogammaglobulinemia NL vaccine response (diphtheria, tetanus, strep, and Hib) | CID with EBV-associated lymphoproliferative disorder and immune dysregulation | Anemia, thrombocytopenia (Pt1) | Aphthous stomatitis, candida stomatitis, EBV, BK polyomavirus infection, P. jirovecii pneumonia (Pt1) EBV (Pt2) | Huck et al., 2009 |
| −/+ | ITK | Homozygous: p.Thr110ArgfsTer155 | Nonsense mediated decay (no protein data shown) | ↓ Total CD3+ ↓ Th17 ↑ Th1 ↑ Treg | ↓ Proliferation after anti-CD3/CD28 | NR | ↑ B | NR | Hodgkin’s lymphoma | NR | EBV, pneumonia | Eken et al., 2019 |
| −/+ | ITK | Homozygous: p.Y588X Predicted to produce kinase dead truncate | Undetectable protein | ↓ Total CD3+ ↓ CD4+ T (Pt2) ↑ CD8+ T (Pt2) ↓ CD8+ T (Pt3) ↓ Naive (Pt2) ↑ Memory (Pt2) ↓ Treg ↓ NKT (Pt3) | ↓ Ca2+ flux | NR | ↑ B | Hypogammaglobulinemia | Hodgkin’s lymphoma | Glomerulonephritis, Tubulointerstitial nephritis (Pt2) | Persistent infectious mononucleosis, including recurrent febrile episodes, lymphadenopathies, extremely high EBV viral load | Stepensky et al., 2011 |
| + | ITK | p.R29H (Pt1) p.D500T, F501L, M503X (Pt2) | Reduced membrane targeting (Pt1) Reduced protein (Pt2) | ↓ Total CD3+ ↓ CD4+ T (Pt1, 2) ↓ CD8+ T ↓ Naive (Pt1, 2) ↑ Memory (Pt2) ↓ NKT (Pt1, 2) | ↓ Ca2+ flux | NR | ↑ B | Hypogammaglobulinemia (Pt1) | B cell lymphoma Proliferative disease (Pt1) Large B cell lymphoma (Pt2): Lymphomatoid granulomatosis | AIHA, ITP (Pt1) | EBV | Linka et al., 2012 |
“− −” indicates absent signal strength, correlating with SCID; “−” indicates near-absent signal strength, correlating with leaky SCID; “−/+” indicates severely reduced signal strength, correlating with CID with significant infections; “+” indicates low but present signal strength, correlating with autoimmunity-predominant CID; “+ +” indicates mildly reduced signal strength, correlating with mainly autoimmunity or mild immunodeficiency; “+ + +” indicates near-normal signal strength, correlating with healthy or minimal clinical impact.
AIHA, autoimmune hemolytic anemia; ALPS, xxx; ARDS, acute respiratory distress syndrome; BCG, Bacillus Calmette-Guérin; GLILD, granulomatous lymphocytic interstitial lung disease; GOF, gain-of-function; HBs, Hepatitis B surface Antigen; Hib, Haemophilus influenzae type b; ITP, immune thrombocytopenia purpura; PJP, P. jirovecii pneumonia; LEQ, Leucine-Glutamate-Glutamine; LOF, loss-of-function; MSSA, methicillin-susceptible Staphylococcus aureus; NR, not reported; NL, normal; Pt, patient; PWM, pokeweed mitogen; RRTI, recurrent respiratory tract infections; TRAV, T cell Receptor Alpha Variable; TREC, T-cell receptor excision circles.