• Test code: 04313
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top EDTA tube (K2EDTA or K3EDTA)
  • Alternate specimens:
    Saliva, assisted saliva, buccal swab and gDNA
  • Sample requirements
  • Request a sample kit

Invitae Familial Mediterranean Fever Test

Test description

The Invitae Familial Mediterranean Fever Test analyzes MEFV, the only gene known to cause familial Mediterranean fever (FMF).

This test is indicated for any individual in whom a diagnosis of FMF is suspected based on clinical symptoms, laboratory findings or positive family history. Additionally, molecular diagnosis is of critical importance in aiding in the diagnosis of symptomatic small children who have a limited ability to articulate and localize symptoms, those with atypical attacks, individuals from non-classically affected ethnic groups, or individuals with milder disease. These presentations may result in a delayed diagnosis and delayed initiation of treatment. Additionally, molecular status can also identify those homozygous for the M694V variant which can confer an increased risk for colchicine resistance and therefore may require supplemental therapies to prevent attacks.

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Primary panel (1 gene)
Add-on Additional Periodic Fever Syndromes Genes (11 genes)

Phenotypic features of FMF can overlap with other periodic fever syndromes. Given the significant phenotypic overlap between these conditions, analyzing other genes associated with periodic fever syndromes may be appropriate. These genes may be included at no additional charge.


Alternative tests to consider

Gene Disorder Protein name Protein symbol
MEFV Familial Mediterranean Fever pyrin PYRIN

Familial Mediterranean fever (FMF) is the most frequent monogenic autoinflammatory disorder and is due to the uncontrolled production of the proinflammatory cytokine interleukin-1β (IL-1β).

FMF is characterized by recurrent attacks of fever and serosal inflammation (inflammation of the serous tissues lining the lungs [pleura], heart and abdomen [peritoneum]) in the absence of an underlying infection. The fevers are often accompanied by pain at other body sites and symptoms have been reported in the following frequency: peritonitis, large joint arthritis with acute synovitis, one-sided pleuritis, and lower extremity myalgia and/or erythema, typically in the lower extremities. Such attacks tend to last 1-3 days before spontaneously resolving. Attacks may occur as frequently as once per week or once every several months with stretches of normal health in between. Attacks occur randomly, without a definite trigger, but may be induced by emotional stress, fatigue, surgery, infection, menstruation, vigorous exercise and/or cold exposure. Onset of symptoms typically occurs prior to ten years of age, with a third of pediatric patients presenting prior to two years of age. Long term complications of FMF include peritoneal adhesions which can lead to intestinal obstruction and female infertility; and a secondary amyloidosis of the gastrointestinal tract, liver, spleen and/or kidney. Amyloidosis of the kidney is the most serious complication and, if untreated, can lead to end stage renal disease.

During an attack, affected individuals demonstrate leukocytosis and elevated acute-phase reactants including ESR, CRP, fibrinogen, haptoglobin, C3, C4 and serum amyloid A (SAA).

Continuous treatment with colchicine has proven successful in preventing attacks in the majority of affected individuals and has even been reported to induce remission in some. Additionally, colchicine therapy can also prevent the long-term risk of amyloidosis. Anti-interleukin 1 treatments are emerging as another potential therapy, especially in those that are nonresponsive, or intolerant, to colchicine.

MEFV is the only known gene to cause familial Mediterranean fever and pathogenic variants are identified in >97% of individuals with a clinical diagnosis of FMF. Thus the absence of FMF pathogenic variants in a symptomatic patient should not exclude a diagnosis and treatment of suspected FMF, or consideration for testing of other periodic fever syndromes. Conversely, biallelic MEFV variants can be found in asymptomatic individuals and once identified, such individuals should be followed closely for consideration of prophylactic therapy.

Four common variants in MEFV: c.442G>C (p.Glu148Gln), c.1105C>T (p.Pro369Ser), c.329T>C (p.Leu110Pro), and c.1223G>A (p.Arg408Gln), are not reported in our Primary report as they are classified as Likely Benign. If present, these variants would be listed in our Supplemental report, which is available upon request.

FMF is inherited in an autosomal recessive and autosomal dominant manner, but is primarily considered an autosomal recessive disease. Most individuals with only one MEFV pathogenic variant are asymptomatic carriers, but approximately one quarter of patients with a clinical diagnosis of FMF are heterozygous for a single MEFV pathogenic variant. Heterozygotes tend to manifest milder disease. Additionally, individuals with two pathogenic MEFV variants have been reported as completely asymptomatic. Given these varying genotypes, the role of modifier genes and environmental factors in the clinical expression of FMF has been strongly suggested.

FMF was originally described among ethnic groups living along the eastern Mediterranean basin but has since been reported in other ethnicities. Prevalence remains highest among populations surrounding the eastern Mediterranean with an estimated prevalence of 6 per 100 individuals in Armenians, 1 per 250 in other populations and and 1 per 40,000 in the United States and western European countries.

Carrier frequency has been reported as high as 37% in the Armenian population and as high as 16% in non-Mediterranean Eastern European countries.

  1. Ter, Haar, N, et al. Treatment of autoinflammatory diseases: results from the Eurofever Registry and a literature review. Ann. Rheum. Dis. 2013; 72(5):678-85. PMID: 22753383
  2. Hofer, M, et al. A child with a systemic febrile illness - differential diagnosis and management. Best Pract Res Clin Rheumatol. 2006; 20(4):627-40. PMID: 16979528
  3. Shohat, M, Halpern, GJ. Familial Mediterranean Fever. 2000 Aug 08. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301405
  4. NORD National Organization for Rare Disorders. Familial Mediterranean Fever
  5. Padeh, S, Berkun, Y. Familial Mediterranean fever. Curr Opin Rheumatol. 2016; 28(5):523-9. PMID: 27286236
  6. Sönmez, HE, et al. Familial Mediterranean fever: current perspectives. J Inflamm Res. 2016; 9:13-20. PMID: 27051312
  7. Brik, R, et al. Familial Mediterranean fever: clinical and genetic characterization in a mixed pediatric population of Jewish and Arab patients. Pediatrics. 1999; 103(5):e70. PMID: 10224214
  8. Koné, Paut, I, et al. Phenotype-genotype correlation in 91 patients with familial Mediterranean fever reveals a high frequency of cutaneomucous features. Rheumatology (Oxford). 2000; 39(11):1275-9. PMID: 11085810
  9. Debeljak, M, et al. The carrier rate and spectrum of MEFV gene mutations in central and southeastern European populations. Clin. Exp. Rheumatol. 2015; 33(6 Suppl 94):S19-23. PMID: 26399837
  10. Touitou, I. The spectrum of Familial Mediterranean Fever (FMF) mutations. Eur. J. Hum. Genet. 2001; 9(7):473-83. PMID: 11464238
  11. Marek-Yagel, D, et al. Clinical disease among patients heterozygous for familial Mediterranean fever. Arthritis Rheum. 2009; 60(6):1862-6. PMID: 19479871

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 and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.

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
ADA2 NM_001282225.1
ELANE NM_001972.2
LPIN2 NM_014646.2
MEFV NM_000243.2
MVK NM_000431.3
NLRC4 NM_021209.4
NLRP12 NM_144687.3
NLRP3 NM_004895.4
PSMB8 NM_148919.3
PSTPIP1 NM_003978.3
TNFRSF1A NM_001065.3
TRNT1 NM_182916.2