Familial Mediterranean Fever (Renal Amyloidosis) via the MEFV Gene

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
7739 MEFV 81404 81404,81479 $640 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
7739MEFV81404 81404(x1), 81479(x1) $640 Order Options and Pricing

Pricing Comments

This test is also offered via our exome backbone with CNV detection (click here). The exome-based test may be higher priced, but permits reflex to the entire exome or to any other set of clinically relevant genes.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Turnaround Time

18 days on average for standard orders or 13 days on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

Amyloidosis is characterized by abnormal deposition of insoluble beta-pleated sheet aggregates (amyloid) of specific plasma proteins, resulting in disruption of organ and tissue function. Deposition can be localized or systemic, be restricted to a single organ or involve multiple organs respectively, with the kidney most frequently affected. Clinically, the presence of proteinuria, renal insufficiency, heart failure, orthostatic hypertension, peripheral neuropathy or unexplained kidney, heart or systemic disease are suspicious for amyloidosis (Picken 2010). Presentation includes a spectrum of symptoms varying from asymptomatic to fatigue, extremity edema, angina or syncope, which is associated with more advanced disease (Leung et al. 2012).

Familial Mediterranean fever (FMF) comprises two phenotypes. Type 1 is characterized by recurrent short episodes of inflammation and serositis including fever, peritonitis, synovitis, pleuritis, and, rarely, pericarditis and meningitis. The symptoms and severity vary among affected individuals, sometimes even among members of the same family. Amyloidosis, which can lead to renal failure, is the most severe complication. Type 2 is characterized by amyloidosis as the first clinical manifestation of FMF in an otherwise asymptomatic individual. The prevalence of amyloidosis varies by ethnicity, genotype, and gender. In untreated individuals, amyloidosis can occur in 60% of individuals of Turkish heritage and in up to 75% of North African Jews (Shohat et al 1999). The age of onset of FMF attacks appears to be earlier in persons with amyloidosis than in those without amyloidosis. FMF-related manifestations of chest pain, arthritis, and erysipelas-like erythema are more common in those with amyloidosis. Diagnosis of FMF is suspected in individuals with recurrent episodes of fever associated with abdominal pain (peritonitis) and/or pleuritic pain and/or arthritis (ankle/knee) usually lasting two to three days. A high erythrocyte sedimentation rate (ESR), leukocytosis, and a high serum concentration of fibrinogen are characteristic (Shohat and Halpern 2012).

Genetics

Familial Mediterranean Fever is inherited in an autosomal recessive manner, caused by mutations in the MEFV gene, although recent studies have suggested that some carriers of single mutations manifest a spectrum of findings from classic FMF to mild FMF. Affected individuals may therefore have biallelic MEFV mutations or a heterozygous MEFV mutation in about 25% of cases (Moradian et al, 2010). Carrier rates for FMF mutations may be as high as 1:3 in some populations, suggesting that the disease is underdiagnosed. The MEFV gene codes for pyrin (also known as marenostrin), which is believed to assist in keeping the inflammation process under control. Pyrin is produced in certain white blood cells (neutrophils, eosinophils, and monocytes) that play a role in inflammation and in fighting infection. MEFV gene mutations lead to reduced amounts of pyrin or a malformed pyrin protein that cannot function properly.

About 80 mutations have been described so far in MEFV gene. The French FMF Consortium (1997) described the most commonly seen Met694Val mutation as the 'MED' variation because it was observed in affected individuals of various ethnic origins (Jewish, Armenian, Turkish, Arabian, non-Ashkanazi Jews) in the Mediterranean basin suggesting founder effect in the origin of a large fraction of FMF cases (El-Shanti et al. 2006). The penetrance of M694V homozygosity was very high (99%) and correlated with a severe disease course. The spectrum of MEFV mutations reported in FMF include missense, nonsense, splicing, regulatory and small deletions/duplications. Five frequent founder mutations accounted for the majority (74%) of mutations, whereas other mutations were found in no more than 1% of FMF chromosomes (Touitou 2001). No gross deletions or insertions have been reported so far (Human Gene Mutation Database). Mutations in MEFV may also be involved in Behçet's disease, Inflammatory bowel disease, Rheumatoid arthritis, Juvenile idiopathic arthritis, Ankylosing spondylitis, Palindromic rheumatism and Systemic lupus erythematosus (SLE) (Shohat and Halpern 2012).

Clinical Sensitivity - Sequencing with CNV PG-Select

MEFV is the only gene known to cause FMF. Five founder mutations, V726A, M694V, M694I, M680I and E148Q account for 74% of FMF chromosomes from typical cases (Armenians, Arabs, Jews, and Turks) whereas other mutations were found in no more than 1% of FMF chromosomes (Touitou 2001).

Testing Strategy

This test provides full coverage of all coding exons of the MEFV gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

Indications for Test

Molecular genetic testing is recommended in individuals with the following clinical manifestations suggesting the diagnosis of familial Mediterranean fever (FMF). The minimal (and most current) criteria for diagnosis of FMF are the Tel Hashomer clinical criteria (Pras 1998). They are: Fever plus EITHER One or more major signs (Fever, Abdominal pain, Chest pain, Joint pain or Skin eruption) and one minor sign OR Two minor signs (increased erythrocyte sedimentation rate, Leukocytosis, elevated serum concentration of fibrinogen). This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in MEFV.

Gene

Official Gene Symbol OMIM ID
MEFV 608107
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Tests

Name
Familial Hemophagocytic Lymphohistiocytosis (FHL) Panel
Periodic Fever Syndromes Panel

Citations

  • Consortium IF. 1997. Ancient Missense Mutations in a New Member of the< i> RoRet Gene Family Are Likely to Cause Familial Mediterranean Fever. Cell 90: 797–807. PubMed ID: 9288758
  • El-Shanti H, Majeed HA, El-Khateeb M. 2006. Familial mediterranean fever in Arabs. Lancet 367: 1016–1024. PubMed ID: 16564365
  • Human Gene Mutation Database (Bio-base).
  • Leung N, Nasr SH, Sethi S. 2012. How I treat amyloidosis: the importance of accurate diagnosis and amyloid typing. Blood 120: 3206–3213. PubMed ID: 22948045
  • Moradian MM, Sarkisian T, Ajrapetyan H, Avanesian N. 2010. Genotype-phenotype studies in a large cohort of Armenian patients with familial Mediterranean fever suggest clinical disease with heterozygous MEFV mutations. J. Hum. Genet. 55: 389–393. PubMed ID: 20485448
  • Picken MM. 2010. Amyloidosis-where are we now and where are we heading? Archives of pathology & laboratory medicine 134: 545–551. PubMed ID: 20367306
  • Pras M. 1998. Familial Mediterranean fever: from the clinical syndrome to the cloning of the pyrin gene. Scand. J. Rheumatol. 27: 92–97. PubMed ID: 9572633
  • Shohat M, Halpern GJ. 2012. Familial Mediterranean Fever. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, and Stephens K, editors. GeneReviews™, Seattle (WA): University of Washington, Seattle. PubMed ID: 20301405
  • Shohat M, Magal N, Shohat T, Chen X, Dagan T, Mimouni A, Danon Y, Lotan R, Ogur G, Sirin A. 1999. Phenotype–genotype correlation in familial Mediterranean fever: evidence for an association between Met694Val and amyloidosis. European Journal of Human Genetics 7: PubMed ID: 10234504
  • Touitou I. 2001. The spectrum of Familial Mediterranean Fever (FMF) mutations. European Journal of Human Genetics 9: 473-483. PubMed ID: 11464238

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page


Specimen Types

Specimen Requirements and Shipping Details

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ORDER OPTIONS

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2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

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Note: acceptable specimen types are whole blood and DNA from whole blood only.
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