NLRP3
8 variant(s) documented across Cryopyrin-Associated Periodic Syndromes, Schnitzler Syndrome
Found across diseases
Variants
| Variant | Type | Frequency in disease | Significance | Also found in |
|---|---|---|---|---|
| Multiple pathogenic variants (>250) | germline | ~50-70% detectable by Sanger | Gain-of-function mutations causing constitutive inflammasome activation. Most in exon 3 (NACHT domain). | Schnitzler syndrome (somatic mosaicism, rare) (Rare); Gout (common variants) (Common) |
| 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. | Schnitzler syndrome (Rare) |
| 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. | — |
| Somatic mosaicism (various) | somatic | Rare (2 confirmed cases) | Found in patients with the most severe phenotypes. Demonstrates that NLRP3 can be directly causative in some cases. | CAPS (Nearly all cases (germline)) |
| V198M | germline | 1 family studied | Found in 1 patient but 4 asymptomatic carriers across 3 generations — insufficient alone to cause disease. | CAPS (mild forms) (Occasional) |
Clinical implications
Multiple pathogenic variants (>250)
Confirms CAPS diagnosis; genotype-phenotype correlation guides prognosis (certain variants → more severe disease).
Testing: Sanger sequencing, targeted gene panels, WES
R260W
Typical MWS phenotype with hearing loss risk.
Testing: Sanger sequencing
T348M
Higher risk of neurological involvement; may require higher dose IL-1 blockade.
Testing: Sanger sequencing
Somatic mosaicism variants
Deep sequencing required for detection; can cause late adult-onset disease.
Testing: Amplicon-based deep sequencing, massively parallel sequencing
De novo mutations
Most NOMID cases are sporadic; genetic counseling important.
Testing: Sanger sequencing, WES
Y861 LRR domain variants
Non-classical presentation; may be missed by clinical criteria alone.
Testing: Sanger sequencing
Somatic mosaicism (various)
Supports inflammasome-driven model. Does not currently change treatment approach.
Testing: deep sequencing, mosaicism-specific assays
V198M
Low-penetrance variant. Not diagnostic on its own.
Testing: Sanger sequencing
Related molecules in pathway
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