Gene test interpretation: MEFV (familial Mediterranean fever gene)

INTRODUCTION — This monograph summarizes the interpretation of germline testing of the MEFV gene, the gene associated with familial Mediterranean fever (FMF).

It does not discuss indications for testing and is not intended to replace clinical judgment in the decision to test or in the clinical care of the individual who was tested. These subjects are discussed separately [1].

OVERVIEW

How to read the report — An approach to reviewing a genetic test report is summarized in the checklist (table 1).

Testing involves two steps: determining the genotype and interpreting the pathogenicity of the variant(s).

●Genotype – Identifies the variants in the gene(s) tested. Genotyping should be repeated in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory if the results were obtained by direct-to-consumer testing or a research study and would impact clinical care (eg, positive finding, negative finding in an individual with a suspected diagnosis or syndrome).

●Interpretation – Determines pathogenicity of the variants identified. (See 'Classification of variants' below.)

The table provides a glossary of genetic testing terms (table 2).

Classification of variants — It is important to review which gene(s) were analyzed and which variants in those genes were tested, as some tests use comprehensive sequencing whereas others only screen for selected genes and/or selected variants.

The pathogenicity of each variant is classified by the testing laboratory into one of five categories based on information available at the time (table 3) [2].

The classification for many variants continues to be updated, especially for variants of uncertain significance (VUSs), as more evidence regarding pathogenicity (or lack thereof) becomes available. The uncertainty in the pathogenicity of variants reflects the current state of information available, rather than the accuracy of genotyping or the likelihood of disease.

If there is concern about the classification, such as for a VUS, obtain an updated interpretation periodically (eg, annually). Updating can be done by checking a database such as ClinVar, contacting the laboratory, or consulting a clinical geneticist, genetic counselor, or other specialist (see 'Locating a genetics expert' below); there is no gold standard approach. Some laboratories routinely provide updates and others require a request. Likely benign and benign variants are not reported (or are reported as negative). Many VUSs are reclassified as benign.

FMF genetics and disease associations

●FMF – Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disorder characterized by recurrent bouts of fever and serosal inflammation. Affected individuals can have recurrent attacks of fever and serositis (eg, peritonitis, pleuritis, pericarditis, synovitis) or erysipelas-like erythema. FMF has a variable expression, possibly due to other genetic and environmental factors. Progressive secondary (AA) amyloidosis is a devastating complication of FMF that may lead to renal failure and death. Recurrent attacks of peritonitis may lead to adhesions and small bowel obstruction.

●MEFV gene – MEFV encodes pyrin, a protein expressed predominantly in myeloid lineage cells, synovial fibroblasts, and dendritic cells. Pyrin appears to act as a specific immune sensor (a pattern recognition receptor for bacterial toxins that modifies Rho GTPase interactions). Pathogenic variants in MEFV cause pyrin gain of function, which can lead to initiation and propagation of the inflammatory cascade even in the absence of provocation by a toxin or infection, resulting in an attack of FMF.

●Common MEFV variants – Seventy-five percent of patients with "prototype FMF" (most of which are in the Middle East, Turkey, Israel, Iraq, Armenia, and Iran) carry pathogenic variants in exon 10 (apart from p.E148Q). These include p.M694V, p.M680I, p.M694I, and p.V726A. p.M694V is the most frequent in Middle Eastern populations, with a prevalence of 20 to 65 percent. However, in Japan, 75 percent of FMF patients carry pathogenic variants in exon 1 to 4 and the only pathogenic variant in exon 10 found in this population is p.M694I rather than p.M694V. Individuals who are homozygous for p.M694V variants tend to have more severe and earlier onset disease; as a result, these individuals may require higher colchicine doses to prevent attacks.

Hundreds of other variants in MEFV have been identified. However, approximately 10 to 20 percent of individuals who meet diagnostic criteria for FMF have no identifiable variants in MEFV. (See "Familial Mediterranean fever: Epidemiology, genetics, and pathogenesis", section on 'Genetics'.)

●Inheritance – In general, FMF is inherited as an autosomal recessive disease (figure 1). Biallelic pathogenic variants in MEFV must be present in the germline for the disease to manifest (homozygous or compound heterozygous).

Individuals who are heterozygous for a pathogenic variant in MEFV are generally asymptomatic carriers, which explains why parents of an affected child may be unaffected and unaware that they carry the variant (figure 2). However, approximately 2 to 5 percent of heterozygous individuals may display FMF, and these individuals account for approximately 33 percent of FMF patients in endemic countries [3,4]. In addition, there are rare cases where FMF is transmitted as an autosomal dominant trait. This pattern of transmission happens with the following MEFV variants: p.M692del, p.H478Y, and p.T577N [5-7]. Additional genetic and environmental modifiers that influence the phenotypic expression of the disease are hypothesized to exist but are not well understood.

●Diagnosis – In endemic countries, the diagnosis of FMF is made on the basis of clinical symptoms and can be supported by ancestry information and family history (algorithm 1 and table 4). Genetic testing for FMF serves to support the diagnosis in patients who meet clinical criteria for FMF, to counsel at-risk relatives, and to guide the therapeutic approach [8]. While ancestry information may affect the determination of disease prevalence, lack of common ancestries cannot be used to exclude the diagnosis of FMF. In countries where FMF is rare, genetic testing has a significant role in diagnosis. (See "Clinical manifestations and diagnosis of familial Mediterranean fever", section on 'Diagnosis'.)

In individuals who meet clinical criteria for FMF but in whom genetic testing is not diagnostic (heterozygosity for a pathogenic variant in MEFV or negative genetic testing), the diagnosis of FMF is supported by a six-month trial of colchicine therapy that results in a relief of attacks and recurrence after cessation of treatment [3]. However, a definitive diagnosis of FMF requires genetic confirmation.

IMPLICATIONS OF A BIALLELIC PATHOGENIC OR LIKELY PATHOGENIC VARIANT — For purposes of counseling, we treat all biallelic (homozygous or compound heterozygous) germline variants in MEFV that are pathogenic or likely pathogenic the same, regardless of the initial reason for testing and the family history (algorithm 2).

Discussion should include:

●Typical symptoms of an attack and how to seek help.

●Long-term complications and preventive strategies.

●Treatment with colchicine, including dosing, adverse effects, and expected response.

●Options for individuals who cannot tolerate colchicine or whose disease does not respond to colchicine.

●Pregnancy and nursing-specific considerations.

Counseling may require additional visits or referral to a genetic counselor or clinical geneticist.

Additional details and supporting evidence are discussed separately. (See "Clinical manifestations and diagnosis of familial Mediterranean fever" and "Management of familial Mediterranean fever".)

HETEROZYGOUS INDIVIDUALS — Approximately 95 to 98 percent of heterozygous individuals are asymptomatic carriers and do not have FMF. However, the remaining 2 to 5 percent of heterozygous individuals meet diagnostic criteria for FMF; these individuals are thought to have other factors that contribute to disease manifestations. (See 'FMF genetics and disease associations' above.)

Heterozygous individuals who meet diagnostic criteria for FMF (table 4) are treated with colchicine similar to those with biallelic pathogenic variants. For rare cases of heterozygous FMF patients who are asymptomatic for several (more than five) years and do not display elevated acute phase reactants, it may be possible to discontinue colchicine. (See "Management of familial Mediterranean fever", section on 'Colchicine'.)

Those who do not meet diagnostic criteria can be counseled that they do not have FMF. However, individuals carrying a single variant may develop FMF late in life (algorithm 2). (See 'Considerations for relatives' below.)

IMPLICATIONS OF A NEGATIVE TEST — Negative testing means that no pathogenic or likely pathogenic variants were identified. However, some tests only query a subset of variants; pathogenic variants might be present in other parts of the gene (if testing was not comprehensive).

Approximately 10 to 20 percent of patients who meet clinical diagnostic criteria for FMF do not carry any pathogenic variants in MEFV [9,10]. In these cases, the diagnosis of FMF is considered probable rather than definitive. Thus, the following considerations apply:

●A negative test cannot be used to exclude FMF in an individual with clinical features of the disease. Additional testing may be indicated, such as more extensive testing of MEFV or testing of other genes (algorithm 2).

●For individuals with a positive family history in which the familial MEFV variants are known and the tested individual does not carry those variants, usually they can be reassured that they are not at high risk for FMF. However, it is important to assess family history to provide an individualized risk assessment. (See 'Locating a genetics expert' below.)

●For individuals with a positive family history in which the familial MEFV variant(s) are not known, the affected individuals should undergo genetic testing first (before unaffected individuals). Referral to a clinical geneticist or genetic counselor may be helpful in determining the optimal testing strategy in those with a family history suggestive of FMF. (See 'Locating a genetics expert' below.)

IMPLICATIONS OF A VARIANT OF UNKNOWN SIGNIFICANCE — Individuals with a variant of uncertain significance (VUS) should be managed based on their personal and family history, their clinical manifestations, and not the VUS (algorithm 2).

New information may become available, and the testing laboratory or other resources should be consulted periodically for updates in the classification (eg, annually).

CONSIDERATIONS FOR RELATIVES

Reproductive counseling — FMF is generally an autosomal recessive disease.

●Children of an affected individual who has biallelic pathogenic variants in MEFV will be obligate carriers of one or the other variant. The children of such an individual could be affected with FMF if their other parent is also a carrier of a disease variant; as a result, such a child may inherit a pathogenic variant in MEFV from both parents. Nevertheless, some children may display FMF even with a single pathogenic variant they inherited from their parent who has biallelic variants.

●Siblings of an individual with FMF whose parents are both unaffected carriers have a 25 percent chance of inheriting a pathogenic variant from both parents and being affected. They have a 50 percent chance of being heterozygous and unaffected and a 25 percent chance of not inheriting either of the pathogenic variants in MEFV. (See 'Heterozygous individuals' above and 'Implications of a biallelic pathogenic or likely pathogenic variant' above.)

At-risk relatives — Individuals who test positive for a pathogenic variant or likely pathogenic variant should inform their at-risk relatives about the importance of genetic counseling and possible testing if they have elevated acute phase reactants that are suggestive of subclinical inflammation.

Full siblings of an individual with biallelic germline MEFV variants have a 25 percent chance of having inherited both MEFV variants and a 50 percent chance of being heterozygous carriers of a single MEFV variant. (See 'Heterozygous individuals' above.)

RESOURCES

UpToDate topics

●FMF:

•Clinical manifestations, diagnosis, and management – (See "Familial Mediterranean fever: Epidemiology, genetics, and pathogenesis" and "Clinical manifestations and diagnosis of familial Mediterranean fever" and "Management of familial Mediterranean fever".)

●Genetics:

•Variant classification – (See "Basic genetics concepts: DNA regulation and gene expression", section on 'Clinical classification of pathogenicity'.)

•Terminology – (See "Genetics: Glossary of terms".)

•Genetic testing – (See "Genetic testing".)

•Genetic counseling – (See "Genetic counseling: Family history interpretation and risk assessment".)

Locating a genetics expert

•Clinical geneticists – American College of Medical Genetics and Genomics (ACMG)

•Genetic counselors – National Society of Genetic Counselors (NSGC)

•National Institutes of Health (NIH) Cancer Genetics Services Directory