TNFRSF1A
5 variant(s) documented across Adult-Onset Still's Disease, TNF Receptor-Associated Periodic Syndrome
Found across diseases
Variants
| Variant | Type | Frequency in disease | Significance | Also found in |
|---|---|---|---|---|
| Rare variants associated with AOSD | germline | Rare; particularly relevant in patients with severe/refractory disease courses | TNFRSF1A is the causative gene for TRAPS (TNF receptor-associated periodic syndrome); its association with AOSD further supports genetic overlap with monogenic autoinflammatory diseases | TRAPS (Causative (autosomal dominant)); Other periodic fevers (Variable) |
| Cysteine-disrupting mutations (multiple) | germline | ~27% of Eurofever patients | High-penetrance pathogenic variants. Disrupt disulfide bonds in CRD1/CRD2 of the TNFR1 extracellular domain. Associated with severe phenotype and high amyloidosis risk (24% vs 2% for non-cysteine). | — |
| T50M (p.Thr79Met) | germline | ~10% of Eurofever patients | Most common high-penetrance pathogenic variant. Affects a conserved hydrogen bond critical for protein folding in CRD1. Despite not disrupting a cysteine, carries high disease penetrance and amyloidosis risk similar to cysteine mutations. | — |
| R92Q (p.Arg121Gln) | germline | ~34% of Eurofever patients (most common variant overall) | Low-penetrance variant of uncertain pathogenic significance. Present in 1.2–4% of healthy Caucasians. Associated with milder disease, shorter episodes, less familial aggregation (19% vs 64%), and higher spontaneous resolution rates. Classified as INSAID Group B (uncertain significance). | Multiple sclerosis (Occasional co-occurrence reported) |
| P46L (p.Pro75Leu) | germline | Low-penetrance, uncertain pathogenicity | Another low-penetrance variant. Found at high frequency in sub-Saharan West African populations. Clinical significance debated — may be a benign polymorphism in some ethnic backgrounds. | — |
Clinical implications
Rare variants associated with AOSD
Patients with TNFRSF1A variants may have more challenging disease courses and higher likelihood of requiring biologic therapy
Testing: Sanger sequencing, Next-generation sequencing
Cysteine-disrupting mutations (multiple)
Aggressive treatment with IL-1 blockade recommended. Intensive SAA monitoring for amyloidosis. Higher penetrance (93%).
Testing: Sanger sequencing, next-generation sequencing panel, whole exome sequencing
T50M (p.Thr79Met)
Classified as pathogenic (INSAID Group A). Requires biologic treatment and amyloidosis surveillance.
Testing: Sanger sequencing, targeted gene panel
R92Q (p.Arg121Gln)
Diagnosis of TRAPS should be made cautiously. Colchicine or NSAIDs may suffice. Amyloidosis risk is very low. Some cases may represent coincidental finding.
Testing: Sanger sequencing, targeted gene panel
P46L (p.Pro75Leu)
Context-dependent interpretation required. May be benign in African populations where allele frequency is high.
Testing: Sanger sequencing, targeted gene panel
Related hypotheses
Genetic susceptibility via HLA polymorphisms and autoinflammatory gene variants predisposes to AOSD
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