Cryopyrin-Associated Periodic Syndromes via the NLRP3 Gene

Cryopyrin-Associated Periodic Syndromes (CAPS) include a group of autoinflammatory diseases due to mutations in the NLRP3 gene. CAPS are rare disorders affecting about 1 in 1,000,000 people primarily in North America and Europe (Kastner 2005).

Familial Cold Autoinflammatory Syndrome (FCAS) is characterized by episodes of fever, urticarial-like rash, and joint pain after exposure to cold temperatures. Most patients initially present with rashes at birth or within the first few months of life. This rash is typically seen first on the face or extremities, and may spread to the rest of the body. Joint pain is typically found within hands, knees and ankles. Other symptoms may include conjunctivitis, sweating, drowsiness, headache and nausea. FCAS episodes are variable and may be triggered by exposure to cold temperatures for only a few minutes or an hour or more. Episodes typically last 12 hours, but may persist up to 3 days. Rarely, patients develop amyloidosis later in life.

Neonatal Onset Multisystem Inflammatory Disease (NOMID), also known as Chronic Infantile Neurologic Cutaneous and Arthropathy (CINCA) syndrome, is the most severe form of recurrent fevers due to mutations in the NLRP3 gene. Initial symptoms include rash typically present at birth which persists throughout life. NOMID is characterized by persistent inflammation damaging the nervous system, skin, and joints. Other symptoms include headaches, seizures, chronic meningitis, intellectual disability, loss of hearing, and loss of vision. Persistent joint inflammation often leads to swelling, cartilage overgrowth leading to short stature, prominent forehead, and protruding eyes. Amyloidosis is seen in <2% of patients. Treatment with IL-1 receptor antagonists has been successful in controlling disease (Farasat et al. 2008).

Muckle-Wells syndrome (MWS) is a rare disease characterized by recurrent and self-limited episodes of fever, urticaria, arthralgia, myalgia (Dodé et al. 2002) and conjunctivitis since childhood, which are related to exposure to cold temperatures. Late-onset sensorineural deafness is also observed. Amyloidosis is the main complication and is found in 25% of cases. Two distinct clinical phenotypes are observed: an 'inflammatory phenotype', most commonly seen in patients diagnosed in childhood characterized by relapsing fever and abdominal pain, and an 'organ -disease' phenotype in patients diagnosed during adulthood characterized by fatigue and hearing loss (Kuemmerle-Deschner et al. 2013).

FCAS, NOMID, and MWS are all autosomal dominant diseases characterized by mutations in the NLRP3 gene. Nearly all the causative mutations identified to date are missense variants within exon 3, affecting protein-protein interactions and protein secondary structure (Aksentijevich et al. 2007; Jesus et al. 2008). Specific mutations within the NLRP3 gene may not allow distinguishing between FCAS, NOMID or MWS as common missense mutations have been found within these disorders despite clinically different phenotypes. This suggests that additional modifier genes are involved in determining the disease spectrum. Patients with FCAS typically have a family history, while NOMID is often due to de novo mutations within the NLRP3 gene (Aksentijevich et al. 2002; Jesus et al. 2008). The NLRP3 gene encodes a protein called cryopyrin, a NOD-like receptor, which is a component of the inflammasome complex. When triggered by a danger signal, assembly of the inflammasome increases Interleukin 1β production to drive inflammation to fight off infections (Fujisawa et al. 2007).

Mutations in NLRP3 have been identified in >85% of patients with FACS and ~60% of patients with NOMID (Aksentijevich et al. 2007). Clinical sensitivity for MWS cannot be estimated because only a small number of patients have been reported. Analytical sensitivity should be high because all mutations reported are detectable by sequencing.

This test provides full coverage of all coding exons of the NLRP3 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).