Table 1.
Monogenic AIDs overview.
| INFLAMMASOMOPATHIES | ||||||
|---|---|---|---|---|---|---|
| DISEASE | GENE | LOCUS | PROTEIN | PATHOGENESIS | CLINICAL HALLMARKS | INHERITANCE |
| FMF | MEFV (NM_000243.2) | 16p13.3 | Pyrin | Gain-of-function mutations causing poor affinity to regulatory proteins (PKN1, PKN2, 14-3-3) -> constitutive activation of pyrin inflammasome | Fever (12–72 h), serositis (abdominal pain, chest pain), non-erosive acute arthritis of large joints, erysipela-like lower extremity rash | AR/AD |
| PAAND | MEFV (S242R mutation) | 16p13.3 | Pyrin | Loss of pyrin inhibition by 14-3-3 protein | Fever, neutrophilic dermatosis, acne, pyoderma gangrenosum, cutaneous abscesses | AD |
| MKD | MVK (NM_000431.4) | 12q24.11 | Mevalonate kinase | ↓ prenylation of proteins, necessary for Rho-A activation and PI3K-mediated inhibition of pyrin inflammasome | Early-onset (<1 year), fever (3–7 days), GI symptoms, arthromyalgia or arthritis, maculo-papular or urticarial rash, aphthous stomatitis, hepatosplenomegaly, cervical adenopathy | AR |
| PAPA | PSTPIP1 (NM_003978.5) | 15q24.3 | CD2-binding protein 1 (CD2-BP1) | Gain-of-function mutations of CD2-BP1, which interacts with pyrin and enhances pyrin inflammasome activation | Pyoderma gangrenosum, arthritis, acne | AD |
| PFIT | WDR1 (NM_017491.5) | 4p16.1 | WD40 repeat protein 1 | Hypomorphic mutation, actin accumulation, pyrin inflammasome dysregulation, ↑ IL18 | fever (up to 7 days), mucosal ulcerations, thrombocytopenia, infections | AR |
| CAPS | NLRP3 (NM_004895.4) | 1q44 | Cryopyrin | Gain-of-function mutations of cryopyrin -> ↑caspase-1 activity -> ↑ active IL-1β | FCAS: cold-triggered episodes of fever, urticaria, conjunctivitis | AD |
| MWS: cold-urticaria, sensorineural hearing loss | ||||||
| CINCA: neonatal onset, urticaria, chronic aseptic meningitis, deforming arthropathy, facial dysmorphia | ||||||
| FCAS4 | NLRC4 (NM_001199138.2) | 2p22.3 | NLRC4 | Gain-of-function mutations, NLRC4 inflammasome hyperactivation, ↑ IL-1β and IL-18 | neonatal-onset, cold-induced urticaria, arthralgia, fever | AD |
| AIFEC | NLRC4 (NM_001199138.2) | 2p22.3 | NLRC4 | NLRC4 inflammasome hyperactivation | Early onset enterocolitis, recurrent MAS | AD |
| FCAS2 | NLRP12 (NM_144687.3) | 19q13.42 | Monarch 1 | ↓ constitutive NF-κB inhibition, ↑ ROS production | cold-induced urticaria, arthralgia, fever | AD |
| DISORDERS OF TUMOR NECROSIS FACTOR (TNF)/NF-κB ACTIVITY | ||||||
| DISEASE | GENE | LOCUS | PROTEIN | PATHOGENESIS | CLINICAL HALLMARKS | INHERITANCE |
| TRAPS | TNFRSF1A (NM_001065.4) | 12p13.31 | TNF receptor superfamily member 1A | Altered intracellular TNFR trafficking, ER stress, ↑ ROS, ↑ NLRP3 inflammasome activation | Fever (>7–14 days), periorbital oedema, conjunctivitis, pseudo-cellulitis rash, abdominal pain, migrating myalgia, arthralgia, chest pain, lymphadenopathy | AD |
| BS | NOD2 (NM_001370466.1) | 3p21 | NOD2/CARD15 | Gain-of-function mutations, ↓ auto-inhibition of NF-κB pathway | < 5 years of age, rash, granulomatous uveitis, symmetrical polyarthritis | AD |
| LUBAC deficiency |
HOIL1 (NM_031229.4) HOIP (NM_017999.5) |
14q12 | HOIL1 HOIP |
Defective deubiquitination, constitutive hyperactivation of NF-κB | fever, immunodeficiency, hepatosplenomegaly, amylopectin-like deposits in muscles | AD AR |
| ORAS | FAM105B (NM_138348.6) | 5p15.2 | Otulin | Loss-of-function mutations, defective deubiquitination, constitutive hyperactivation of NF-κB | Onset < 3 months, fever, diarrhoea, arthritis, lipodystrophy, panniculitis, growth restriction | AR |
| HA20 | TNFAIP3 (NM_001270508.2) | 6q23.3 | A20 | Loss-of-function mutations, defective deubiquitination, constitutive hyperactivation of NF-κB | Fever, oral, GI and genital ulcerations, arthritis, uveitis (dd Behcet’s disease) | AD |
| OTHER MONOGENIC AIDs | ||||||
| DISEASE | GENE | LOCUS | PROTEIN | PATHOGENESIS | CLINICAL HALLMARKS | INHERITANCE |
| DADA2 | CERC1 (NM_001282225.2) | 22q11.1 | ADA2 | Macrophage differentiation towards M1 pro-inflammatory activity, IFN signature | Fever, vasculitis (livedo reticularis, ulcers), stroke, cytopenias, hypogammaglobulinemia | AR |
| DIRA | IL1RN (NM_173841.2) | 2q14.1 | IL1Ra | ↓ IL-1α and IL-1β inhibition | Pustular rash, multifocal osteomyelitis, periostitis | AR |
| DITRA | IL36RN (NM_173170.1) | 2q14.1 | IL36Ra | ↓ NF-κB inhibition, hyperinflammation in keratinocytes | Pustular psoriasis, fever, neutrophilia | AR |
| TYPE I INTERFERONOPATHIES | ||||||
| DISEASE | GENE | LOCUS | PROTEIN | PATHOGENESIS | CLINICAL HALLMARKS | INHERITANCE |
| AGS 1 | TREX-1 (NM_130384.3) | 3p21.31 | 3′-5′ DNA exonuclease | Accumulation of nucleic acids | Basal ganglia calcifications, delayed psycho-motor development, epilepsy (classic AGS) | AR /AD |
| AGS2 | RNASEH2B (NM_001142279.2) | 13q14.3 | RNAse H2 complex. RNA-DNA hybrids degradation |
Classic AGS | AR | |
| AGS3 | RNASEH2C (NM_182710.3) | 11.q.13.1 | Classic ASG | AR | ||
| AGS4 | RNASEH2A (NM_006397.3) | 19p13.13 | ASG + dysmorfic features | AR | ||
| AGS5 | SAMHD1 (NM_080628.3) | 20q11.23 | SAM domain and HD domain-containing protein 1 (restricts the availability of deoxynucleotides) | Severe neurological involvement with early stroke, arthropathy | AR | |
| AGS6 | ADAR (NM_001111.5) | 1q21.3 | adenosine deaminase, RNA-specific | ASG, bilateral striatal necrosis | AR/AD | |
| AGS7 | IFIH1 (NM_022168.4) | 2q24.3 | Interferon Induced with Helicase C Domain 1 (Cytosolic receptor for dsRNA) | Mild AGS | AD | |
| C1QA/B/C | C1q (NM_015991.4) | 1p36.12 | Complement—Classic pathway | Complement pathway dysregulation | SLE, early nefritis and infectious susceptibility | AR |
| C1r/s | C1r (NM_001733.7) | 12p13.31 | ||||
| C2 | C2 (GRCh38: 6:31,897,782-31,945,671) | 6p21.33 | ||||
| C4 a/b | C4 (GRCh38: 6:31,982,056-32,002,680) | 6p21.33 | ||||
| C3 | C3 (GRCh38: 19:6,677,703-6,720,649) | 6p21.33 | ||||
| DNASE1L3 | DNAsi1L3 (NM_004944.4) | 3p14.3 | DNAsi1L3 | Extracellular acid nucleic degradation alteration | SLE, early onset, nephritis, ANCA positive hypocomplementemic urticarial vasculitis syndrome (HUVS) | AR |
| DNASE 2 |
DNAsi 2 (GRCh38: 19:12,875,208-12,881,448) |
19p13.13 | DNAsi 2 | Endonuclease dysregulation | SLE antibodies + pancitopenia, membranoproliferative glomerulonephritis, liver fibrosis, deforming arthropathy | AR |
| IFIHI | MDA5 (NM_022168.4) | 2q24.3 | melanoma differentiation-associated protein 5 | Mutations of type- I IFN Cytosolic sensor for dsRNA | SLE, IgA deficiency, mild lower limb | AD |
| TREX1 | TREX1 (NM_130384.3) | 3p21.31 | Three Prime Repair Exonuclease 1 | Mutations of Type-I IFN degradation of intracellular ds-ss DNA | FCL | AD |
| SAMHD1 | SAMHD1 (NM_080628.3) | 20q11.23 | SAMHD1 | Mutations of Type I IFN cytoplasmic ssRNA/DNA sensor | FCL | AR |
| SAVI | STING (NM_198282.4) | 5q31.1 | Stimulator of interferon gene | Gain-of-function mutations, ↑ type I IFN pathway | Skin vasculopathy, bilateral interstitial lung disease | AD |
| PRAAS | PSMA3/PSMB8 | 14q23.1/6p21.32 | Proteasome complex subunit Proteosome chaperone |
Loss-of-function mutations in proteasome components, causing type I IFN pathway upregulation | CANDLE syndrome: Chronic Neutrophilic Dermatosis panniculitis with Lipodystrophy, Elevated Temperature |
AR |
| PSMB4/PSMB9 | 1q21.3/6p21.321q21.3/6p21.32 | |||||
| PSMB4/PSMB8 | 6p21.32 | |||||
| PSMB9 (GRCh38: 6:32,854,191-32,859,850) | 16q22.1 | |||||
| PSMB10 (GRCh38: 16:67,934,505-67,936,849) | 9q33.3 | |||||
| PSMB7 (GRCh38: 9:124,353,464-124,415,441) | 14q23.1 | |||||
| PSMA3 (GRCh38: 14:58,244,842-58,272,003) | 13q12.3 | |||||
| POMP (GRCh38: 13:28,659,129-28,678,958) | 1 | |||||
| PSMG2 (GRCh38: 18:12,658,737-12,725,739) | 8p11.21 | |||||
| ISG15 deficiency | ISG15 (NM_005101.4) | 1p31.33 | Interferon-stimulated gene 15 (Stabilizes USP18) | Neurological involvement, mycobacterial susceptibility | AR | |
| USP18 deficiency | UDP18 (NM_019076.4) | 2q37.1 | UDP18 | Altered inhibition of IFNR signalling | Neurological involvement, hepatomegaly, thrombocytopenia | AD |
| SMS |
IFIH1 DDX58 (NM_014314.4) |
2q24.3 9p21.1 |
IFIH1 DExD/H-Box Helicase 58 |
Mutations of a cytosolic receptor for dsRNA | Dental and skeletal dysplasia, aortic calcification, glaucome and psoriasis | AD |
Abbreviations: AIFEC (autoinflammations and infantile enterocolitis).