Table 2.
Autoinflammatory diseases caused by mutations in genes encoding essential TNF signalling proteins
| Gene symbol | Protein name | Disease mechanism | Patient phenotype | OMIM entry | Refs. |
|---|---|---|---|---|---|
| CASP8 | Caspase 8 | Homozygous, loss of function | Autoimmune lymphoproliferative syndrome; very early onset IBD | 607271 | 95,96 |
| IKBKG | NEMO | Loss of function | Incontinentia pigmenti in heterozygous females (lethal in males); immunodeficiency; EDA-ID | 308300 | 147 |
| IKBKG | NEMO | Carboxy-terminal deletions in NEMO | Inflammatory skin and intestinal disease; ectodermal dysplasia with anhidrosis and immunodeficiency | NA | 139 |
| IKBKG | NEMO | NEMO lacking the domain encoded by exon 5 | Severe autoinflammatory syndrome; NDAS | 301081 | 148,149 |
| OTULIN | OTULIN | Homozygous, loss of function | Early-onset recurrent fever; neutrophilic dermatitis/panniculitis, joint swelling; ORAS | 617099 | 122–125 |
| OTULIN | OTULIN | Compound heterozygous variants | Atypical late-onset ORAS | NA | 126 |
| RBCK1 | HOIL1 | Homozygous, loss of function | Severe multi-organ autoinflammation, immunodeficiency, invasive bacterial infections, muscular amylopectinosis | 615895 | 120 |
| RELA | RelA | Haploinsufficiency | Fever, abdominal pain, mucocutaneous lesions | 618287 | 152 |
| RIPK1 | RIPK1 | Homozygous, loss of function | Recurrent infections, early-onset IBD, progressive polyarthritis, immunodeficiency | 618108 | 168,169 |
| RIPK1 | RIPK1 | Heterozygous mutation of the RIPK1 caspase 8 cleavage site | Early-onset periodic fever syndrome and lymphadenopathy; CRIA | 618852 | 52,53,103 |
| RNF31 | HOIP | Homozygous, loss of function | Severe multi-organ autoinflammation, immunodeficiency | NA | 119,121 |
| TBK1 | TBK1 | Homozygous, loss of function | Chronic and systemic autoinflammation | NA | 157 |
| TNFAIP3 | A20 | Haploinsufficiency | Early-onset severe multiorgan autoinflammatory syndrome; HA20 | 616744 | 137,138 |
| XIAP | XIAP | Loss of function | Pathogen-associated hyperinflammation, fever, severe IBD; XLP2 | 300635 | 107 |
Details of the genetic disorders can be found in OMIM. CRIA, cleavage-resistant receptor-interacting serine/threonine protein kinase 1 (RIPK1)-induced autoinflammatory syndrome; EDA-ID, anhidrotic ectodermal dysplasia with immune deficiency; HA20, haploinsufficiency of A20; IBD, inflammatory bowel disease; NA, not available; ORAS, OTULIN-related autoinflammatory syndrome; NDAS, nuclear factor-κB essential modulator (NEMO) deleted exon 5–autoinflammatory syndrome; TBK1, TANK-binding kinase 1; XIAP, X-linked inhibitor of apoptosis protein; XLP2, X-linked lymphoproliferative syndrome 2.