CAPS diseases are associated with mutations or misspellings in the Nucleotide-binding domain, leucine rich family (NLR), pyrin containing 3 gene (NLRP3) also known as the Cold-Induced Auto inflammatory Syndrome 1 (CIAS1 ) gene. It is also referred to as the NALP3 or PYPAF1 gene in some literature.
NLRP3 encodes cryopyrin, which belongs to an emerging family of danger sensors, called NLRs (NOD-like receptors). When triggered by a danger signal, cryopyrin assembles with other molecules to coordinate an inflammatory response that leads to increased Interleukin-1ß (IL-1ß) production to help fight off infections. This sensing and coordinating unit is called an "inflammasome."
A mutation of the NLRP3 gene causes the cryopyrin inflammasome to constantly overproduce IL-1ß instead of producing IL-1ß only in response to infections. This overproduction of IL-1ß causes many CAPS symptoms to be present at birth or in early infancy, and persist or increase throughout life.
Rashes, fevers, joint pain, headaches, conjunctivitis and many other symptoms are noted with CAPS. The NLRP3 (CIAS1) genetic mutation is autosomal dominant, so only one misspelled gene is needed in a person's DNA to cause CAPS. Misspellings of the NLRP3 gene can occur spontaneously at conception, as is often the case with NOMID/CINCA, and some with MWS. But in FCAS and most with MWS, the gene mutation is usually passed down by one affected parent for many generations.
There is a 50% chance that a parent with CAPS will pass the NLRP3 gene mutation onto their child. The dominant NLRP3 mutation DOES NOT require two parents to have the mutation to pass the syndrome genetically to their offspring - only one person with the mutation can cause CAPS to be passed on the next generation. Most families with CAPS usually have FCAS or MWS, and share common symptoms or severity, but sometimes there can be a variable level of expression of CAPS symptoms within large family groups with the CIAS1 gene mutation. ANY patient with a CAPS mutation (including NOMID) can pass it on genetically to their offspring.
NLRP3 (CIAS1) gene mutations are present in most patients with FCAS or MWS, but in the past, 40% of patients that had clinical symptoms typical of NOMID did not have detectable NLRP3 mutations on genetic tests. However, new research, and improved genetic testing methods have now made it possible to find NLRP3 mutations in most of these patients.
A clinical diagnosis based on symptoms still is essential. The proper diagnosis of CAPS should include genetic testing for NLRP3 (CIAS1) and other auto inflammatory disorders, along with a full evaluation of symptoms, lab tests, a skin biopsy, and a complete medical history from birth onwards. Genetic tests for other auto inflammatory disorders may also be helpful in diagnosis.
In recent years, some researchers have found cases of somatic mosaicism of the NLRP3 (CIAS1) gene mutation in many cases of NOMID/CINCA that had been previously found to have the clinical findings for these syndromes, without evidence of the genetic mutation on the standard genetic tests.
In most cases of CAPS, or other diseases caused by mutations or misspelling of gene, a person has only one set of DNA in their body, and that DNA is present in all their tissues. A very small number of people have somatic mosaicism, meaning that in their body they have more than one distinct DNA code for their body.
Somatic mosaicism of the NLRP3 (CIAS1) gene occurs either right after the fertilized egg (zygote) has divided into two cells, or at any stage later in early cellular development of an individual. During cellular division, the cell divides differently, creating more than one distinct form of DNA. So, when that cell divided, one set of DNA became different than the original cell's DNA. If a genetic mutation happens during this process, such as with the NLRP3 (CIAS1) gene, a person could have some DNA carrying a mutation for CAPS in their body, and other cells with different DNA that does not have that gene mutation. Individuals with somatic mosaicism can have two, or more different, and distinct DNA codes in their body that can be widespread throughout all the tissues and organs, or in some cases, there may be certain DNA codes in some tissues, and a different DNA code present in other tissues or organs in the body. So a person with somatic mosaicism may have different "penetrance" of the amount of DNA in the tissues in their body that contains the NLRP3 (CIAS1 mutation, instead of every cell having the same DNA and the gene mutation in all tissues