• Test code: 08121
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit

Invitae Familial Cold Autoinflammatory Syndrome Panel

Test description

Invitae Familial Cold Autoinflammatory Syndrome Panel analyzes four genes that are associated with familial cold autoinflammatory syndrome (FCAS). Genetic testing of these genes may confirm a diagnosis and help guide treatment and management decisions. Identification of a disease-causing variant would also guide testing and diagnosis of at-risk relatives.

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Primary panel (4 genes)

Gene Disorder Protein name Protein symbol
NLRC4 NLRC4-MAS (macrophage activation syndrome), Familial cold autoinflammatory syndrome 4 NLR family, CARD containing 4 NLRC4
NLRP12 Familial cold autoinflammatory syndrome 2 NACHT domain-, leucine-rich repeat-, and PYD-containing protein 12 NALP12
NLRP3 Muckle-Wells syndrome, Familial cold autoinflammatory syndrome 1, Neonatal onset multisystem inflammatory disease (NOMID) or chronic infantile neurologic cutaneous and articular syndrome (CINCA) cryopyrin cryopyrin
PLCG2 PLAID (PLCγ2 associated antibody deficiency and immune dysregulation), Familial cold autoinflammatory syndrome 3, APLAID (autoinflammation and PLCγ2 associated antibody deficiency and immune dysregulation) phospholipase C gamma 2 PLCG2

Familial cold autoinflammatory syndrome is part of a clinical spectrum referred to as cryopin associated periodic syndrome. Other disorders included in this spectrum include neonatal onset multi-inflammatory disorder (NOMID) and Muckle–Wells syndrome (MWS). Familial cold autoinflammatory syndrome causes an inflammatory reaction in the absence of infection or autoimmune disease. It is characterized by infantile-onset, non-itchy rash, episodic fever, and joint pain following exposure to cold stimuli. Conjunctivitis is also frequently reported. Clinical symptoms typically present within 1-2 hours of cold exposure and last less than 24 hours, but may lead to overwhelming fatigue in the long term. Patients with MWS may develop hearing loss, kidney damage due to amyloidosis and pigmented skin lesions. Hearing loss in MWS and NOMID can be restored in some cases with anti-interleukin -1 therapy.

NLRC4, NLRP3, NLRP12, and PLCG2 are the only genes known to be associated with FCAS. However, due to the rarity of this condition, the percent of FCAS attributed to pathogenic variants in these genes is currently unknown.

Familial cold autoinflammatory syndrome is inherited in an autosomal dominant manner.

Familial cold autoinflammatory syndrome is most commonly reported in individuals of European descent and is considered very rare. Prevalence was estimated to be 1:1,000,000 individuals in a study of Australian individuals.

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
NLRC4 NM_021209.4
NLRP12 NM_144687.3
NLRP3 NM_004895.4
PLCG2 NM_002661.4