Table 1.
Immunodeficiencies affecting cellular and humoral immunity
| Disease | Genetic defect | Inheritance | OMIM | T cells | B cells | Ig | Associated features |
|---|---|---|---|---|---|---|---|
| 1. T-B+ severe combined immune deficiency (SCID) | |||||||
| γc deficiency (common gamma chain SCID, CD132 deficiency) | IL2RG | XL | 308380 | Very low | Normal to high | Low | Low NK |
| JAK3 deficiency | JAK3 | AR | 600173 | Very low | Normal to high | Low | Low NK |
| IL7Rα deficiency | IL7R | AR | 146661 | Very low | Normal to high | Low | Nl NK |
| CD45 deficiency | PTPRC | AR | 151460 | Very low | Normal | Low | Nl γ/δ Τ cells |
| CD3δ deficiency | CD3D | AR | 186790 | Very low | Normal | Low | Nl NK, no γ/δ T cells |
| CD3ε deficiency | CD3E | AR | 186830 | Very low | Normal | Low | Nl NK, no γ/δ T cells |
| CD3ζ deficiency | CD247 | AR | 186780 | Very low | Normal | Low | Nl NK, no γ/δ T cells |
| Coronin-1A deficiency | CORO1A | AR | 605000 | Very low | Normal | Low | Detectable thymus, EBV |
| LAT deficiency | LAT | AR | 602354 | Nl to low number | Nl to low | High | Adenopathy, splenomegaly, recurrent infections, autoimmunity |
| 2. T-B- SCID | |||||||
| RAG1 deficiency | RAG1 | AR | 179615 | Very low | Very low | Decreased | Nl NK |
| RAG2 deficiency | RAG2 | AR | 179616 | Very low | Very low | Decreased | Nl NK |
| DCLRE1C (Artemis) deficiency | DCLRE1C | AR | 605988 | Very low | Very low | Decreased | Nl NK, radiation sensitive |
| DNA PKcs deficiency | PRKDC | AR | 176977 | Very low | Very low | Variable | Nl NK, radiation sensitive, microcephaly |
| Cernunnos/XLF deficiency | NHEJ1 | AR | 611290 | Very low | Very low | Decreased | Nl NK, radiation sensitive, microcephaly |
| DNA ligase IV deficiency | LIG4 | AR | 601837 | Very low | Very low | Decreased | Nl NK, radiation sensitive, microcephaly |
| Reticular dysgenesis | AK2 | AR | 103020 | Very low | Nl to low | Decreased | Granulocytopenia and deafness |
| Adenosine deaminase (ADA) deficiency | ADA | AR | 608958 | Very low | Low, decreasing | Low, decreasing | Low NK, bone defects, may have pulmonary alveolar proteinosis, cognitive defects |
| 3. Combined immunodeficiencies generally less profound than severe combined immunodeficiency | |||||||
| DOCK2 deficiency | DOCK2 | AR | 603122 | Low | Normal | IgG Nl or low, poor antibody responses | Nl NK cells, but defective function. Poor interferon responses in hematopoietic and non-hematopoietic cells |
| CD40 ligand deficiency (CD154) | CD40LG (TNFSF5) | XL | 300386 | Nl to low | sIgM+, IgD+ cells present, absent sIgG+, IgA+, and IgE+ cells | IgM normal or high, other Ig isotypes low | Neutropenia, thrombocytopenia, hemolytic anemia, opportunistic infections, biliary tract and liver disease, Cryptosporidium infections |
| CD40 deficiency | CD40 (TNFRSF5) | AR | 109535 | Normal | sIgM+, IgD+ cells present, absent sIgG+, IgA+ and IgE+ cells | IgM normal or high, other Ig isotypes low | Neutropenia, opportunistic infections, gastrointestinal and biliary tract and liver disease, Cryptosporidium infections |
| ICOS deficiency | ICOS | AR | 604558 | Normal | Normal | Low | Recurrent infections, autoimmunity, gastroenteritis, granulomas |
| CD3γ deficiency | CD3G | AR | 186740 | Nl number, but low TCR expression | Normal | Normal | |
| CD8 deficiency | CD8A | AR | 186910 | Absent CD8, nl CD4 | Normal | Normal | Recurrent infections, may be asymptomatic |
| ZAP-70 deficiency (ZAP70 LOF) | ZAP70 | AR | 176947 | Low CD8, Nl CD4 number but poor function | Normal | Normal | May have immune dysregulation, autoimmunity |
| MHC class I deficiency | TAP1 | AR | 170260 | Low CD8, Nl CD4, absent MHC I on lymphocytes | Normal | Normal | Vasculitis, pyoderma gangrenosum |
| MHC class I deficiency | TAP2 | AR | 170261 | Low CD8, Nl CD4, absent MHC I on lymphocytes | Normal | Normal | Vasculitis, pyoderma gangrenosum |
| MHC class I deficiency | TAPBP | AR | 601962 | Low CD8, Nl CD4, absent MHC I on lymphocytes | Normal | Normal | Vasculitis, pyoderma gangrenosum |
| MHC class I deficiency | B2M | AR | 109700 | Low CD8, Nl CD4, absent MHC I on lymphocytes | Normal | Normal | Sinopulmonary infections, cutaneous granulomas. Absent β2m associated proteins MHC I, CD1a, CD1b, CD1c |
| MHC class II deficiency group A | CIITA | AR | 600005 | Low CD4 cells Absent MHC II expression on lymphocytes |
Normal | Nl to low | Respiratory and gastrointestinal infections, liver/biliary tract disease |
| MHC class II deficiency group B | RFXANK | AR | 603200 | Low CD4 cells Absent MHC II expression on lymphocytes |
Normal | Nl to low | Respiratory and gastrointestinal infections, liver/biliary tract disease |
| MHC class II deficiency group C | RFX5 | AR | 601863 | Low CD4 cells Absent MHC II expression on lymphocytes |
Normal | Nl to low | Respiratory and gastrointestinal infections, liver/biliary tract disease |
| MHC class II deficiency group D | RFXAP | AR | 601861 | Low CD4 cells Absent MHC II expression on lymphocytes |
Normal | Nl to low | Respiratory and gastrointestinal infections, liver/biliary tract disease |
| DOCK8 deficiency | DOCK8 | AR | 243700 | Low, poor proliferation, few, poorly functioning Treg | Low, low CD27+ memory B cells Poor peripheral B cell tolerance | Low IgM, Nl to high IgG and IgA, high IgE | Low NK cells with poor function, eosinophilia, recurrent infections, cutaneous viral, fungal and staphylococcal infections, severe atopy, cancer diathesis |
| Rhoh deficiency | RHOH | AR | 602037 | Nl number, low naïve T cells, restricted repertoire, poor proliferation to CD3 | Normal | Normal | HPV infection, lung granulomas, molluscum contagiosum, lymphoma |
| MST1 deficiency | STK4 | AR | 614868 | Low, low terminal differentiated effector memory (TEMRA) cells, low naïve T cells, poor proliferation | Low | High | Intermittent neutropenia, bacterial, viral (HPV), candidal infections, EBV lymphoproliferation, autoimmune cytopenias, lymphoma, congenital heart disease |
| TCRα deficiency | TRAC | AR | 615387 | Absent TCRαβ, all T cells are γδ, poor proliferation | Normal | Normal | Recurrent viral, bacterial, fungal infections, immune dysregulation and autoimmunity, diarrhea |
| LCK deficiency | LCK | AR | 615758 | Low CD4+, low Treg, restricted T cell repertoire, poor TCR signaling | Normal | Nl IgG and IgA, high IgM | Recurrent infections, immune dysregulation, autoimmunity |
| MALT1 deficiency | MALT1 | AR | 615468 | Nl number, poor proliferation | Normal | Nl levels, poor specific antibody response | Bacterial, fungal and viral infections |
| CARD11 deficiency (LOF) | CARD11 | AR | 615206 | Nl number, predominant naïve T cells, poor proliferation | Normal, transitional B cell predominance | Absent/low | Pneumocystis jirovecii pneumonia, bacterial and viral infections |
| BCL10 deficiency | BCL10 | AR | 616098 | Nl number, low memory T and Treg cells, poor antigen and anti-CD3 proliferation | Nl number, decreased memory and switched B cells | Low | Recurrent bacterial and viral infections, candidiasis, gastroenteritis |
| BCL11B deficiency | BCL11B | AD | 617237 | Low, poor proliferation | Normal | Normal | Congenital abnormalities, neonatal teeth, dysmorphic facies, absent corpus callosum, neurocognitive deficits |
| IL-21 deficiency | IL21 | AR | 615767 | Nl number, nl/low function | Low | Low IgG | Severe early-onset colitis, recurrent sinopulmonary infections |
| IL-21R deficiency | IL21R | AR | 615207 | Nl number, low cytokine production, poor antigen proliferation | Normal | Nl number, poor specific antibody responses | Recurrent infections, Pneumocystis jiroveci, Cryptosporidium infections and liver disease |
| OX40 deficiency | TNFRSF4 | AR | 615593 | Nl numbers, low antigen specific memory CD4+ | Nl numbers, low memory B cells | Normal | Impaired immunity to HHV8, Kaposi’s sarcoma |
| IKBKB deficiency | IKBKB | AR | 615592 | Nl number, absent Treg and γ/δ T cells, impaired TCR activation | Nl number, poor function | Low | Recurrent bacterial, viral, fungal infections, opportunistic infections |
| NIK deficiency | MAP3K14 | AR | 604655 | Nl number, poor proliferation to antigen | Low, low switched memory B cells | Low Ig’s | Low NK number and function, recurrent bacterial, viral and Cryptosporidium infections |
| RelB deficiency | RELB | AR | 604758 | Nl number, poor diversity, poor function | Recurrent infections | ||
| Moesin deficiency | MSN | XL | 300988 | Nl number, defective migration, proliferation | Low number | Low Ig’s over time | Recurrent infections with bacteria, varicella, neutropenia |
| TFRC deficiency | TFRC | AR | 616740 | Nl number, poor proliferation | Nl number, low memory B cells | Low | Recurrent infections, neutropenia, thrombocytopenia |
SCID/CID spectrum: Infants with SCID who have maternal T cell engraftment may have T cells in normal numbers that do not function normally; these cells may cause autoimmune cytopenias or graft versus host disease. Hypomorphic mutations in several of the genes that cause SCID may result in Omenn syndrome (OS), or “leaky” SCID, or still less profound combined immunodeficiency (CID) phenotypes. Both OS and leaky SCID can be associated with > 300 autologous T cells/μL of peripheral blood and reduced, rather than absent, proliferative responses when compared with typical SCID caused by null mutations. A spectrum of clinical findings including typical SCID, OS, leaky SCID, CID, granulomas with T lymphopenia, autoimmunity and CD4 T lymphopenia can be found in an allelic series of RAG1 and other SCID-associated genes. Total number of disorders in Table 1: 49 (17 SCID, 32 CID). New disorders: 5, MOESIN, BCL11B, TFRC, RELB, LAT. Removed gene: UNC119 deficiency has been removed. The UNC119 variant reported previously is a benign polymorphism in unaffected individuals
SCID severe combined immunodeficiency, EBV Epstein-Barr virus, MHC major histocompatibility complex, HPV human papillomavirus, Treg T regulatory cell, Nl normal, XL X-linked inheritance, AR autosomal recessive inheritance, AD autosomal dominant inheritance, LOF loss-of-function