Invitae Familial Mediterranean Fever Test

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  • Test code: 04313
  • 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
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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)

MEFV

Add-on additional periodic fever syndromes genes (5 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.

LPIN2 MVK NLRP3 PSTPIP1 TNFRSF1A

Alternative tests to consider

  • familial Mediterranean fever (FMF)

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.

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. 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
  2. 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
  3. 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
  4. 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
  5. Marek-Yagel, D, et al. Clinical disease among patients heterozygous for familial Mediterranean fever. Arthritis Rheum. 2009; 60(6):1862-6. PMID: 19479871
  6. NORD National Organization for Rare Disorders. Familial Mediterranean Fever
  7. Padeh, S, Berkun, Y. Familial Mediterranean fever. Curr Opin Rheumatol. 2016; 28(5):523-9. PMID: 27286236
  8. Shohat, M, Halpern, GJ. Familial Mediterranean Fever. 2000 Aug 08. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301405
  9. Sönmez, HE, et al. Familial Mediterranean fever: current perspectives. J Inflamm Res. 2016; 9:13-20. PMID: 27051312
  10. 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
  11. Touitou, I. The spectrum of Familial Mediterranean Fever (FMF) mutations. Eur. J. Hum. Genet. 2001; 9(7):473-83. PMID: 11464238

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, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
LPIN2 NM_014646.2
MEFV NM_000243.2
MVK NM_000431.3
NLRP3 NM_004895.4
PSTPIP1 NM_003978.3
TNFRSF1A NM_001065.3