Familial Mediterranean Fever (Renal Amyloidosis) via the MEFV Gene

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).

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).

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).

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.