NLRP3
Genetic findings for NLRP3 in Cryopyrin-Associated Periodic Syndromes
Variants (6)
| Variant | Type | Frequency | Significance |
|---|---|---|---|
| Multiple pathogenic variants (>250) | germline | ~50-70% detectable by Sanger | Gain-of-function mutations causing constitutive inflammasome activation. Most in exon 3 (NACHT domain). |
| R260W | germline | Common MWS variant | Most frequent MWS-associated variant in French population. |
| T348M | germline | Common in severe CAPS | Associated with early onset, chronic course, hearing loss. |
| Somatic mosaicism variants | somatic | 40% of mutation-negative CAPS | Low-level allele frequency (1.9–45%); can increase over time. Explains 'mutation-negative' CAPS. |
| De novo mutations | germline | ~50-60% of NOMID | Spontaneous new mutations; no family history. |
| Y861 LRR domain variants | germline | Rare | Atypical phenotype with minimal cold-triggered rash. |
Clinical implications
Multiple pathogenic variants (>250)
Confirms CAPS diagnosis; genotype-phenotype correlation guides prognosis (certain variants → more severe disease).
Also found in: Schnitzler syndrome (somatic mosaicism, rare) (Rare), Gout (common variants) (Common)
R260W
Typical MWS phenotype with hearing loss risk.
T348M
Higher risk of neurological involvement; may require higher dose IL-1 blockade.
Somatic mosaicism variants
Deep sequencing required for detection; can cause late adult-onset disease.
Also found in: Schnitzler syndrome (Rare)
De novo mutations
Most NOMID cases are sporadic; genetic counseling important.
Y861 LRR domain variants
Non-classical presentation; may be missed by clinical criteria alone.
Related molecules
Inflammasome sensor and scaffold — mutated
Related hypotheses
NLRP3 gain-of-function mutations cause constitutive inflammasome activation driving IL-1β-mediated autoinflammation in CAPS
98Somatic NLRP3 mosaicism explains disease in a subset of 'mutation-negative' CAPS patients
72Cold-induced cryo-sensitive aggregation of mutant NLRP3 explains FCAS triggering
38Modifier genes and epigenetic factors determine CAPS severity within shared genotypes
35