Version July 2025
INTRODUCTION —
This monograph summarizes the interpretation of germline testing of the MEFV gene, responsible for 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 care for the tested individual. These subjects are discussed separately in UpToDate [1].
OVERVIEW
How to read the report — The checklist summarizes an approach to reviewing a genetic test report (table 1).
Testing involves two steps: determining the genotype and interpreting the pathogenicity of the variant(s) identified.
●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).
Some tests use comprehensive sequencing, whereas others only screen for selected variants.
●Interpretation – Determines pathogenicity of the variants identified. (See 'Classification of variants' below.)
The table provides a glossary of genetics terms (table 2).
Classification of variants — The pathogenicity of each variant is classified by the testing laboratory into one of five categories based on information available when testing was performed (table 3) [2]. Likely benign and benign variants are not reported (or are reported as negative).
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 a VUS reflects the current state of information, not the accuracy of genotyping or 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 at the National Library of Medicine (NLM).
●Checking the Registry of Hereditary Auto-inflammatory Disorders database, Infevers.
●Contacting the laboratory. Some laboratories routinely provide updates and others require a request.
●Consulting a clinical geneticist, genetic counselor, or other specialist. (See 'Locating a genetics expert' below.)
Many VUSs are reclassified as benign.
MEFV gene — MEFV encodes pyrin, a protein expressed predominantly in myeloid lineage cells, synovial fibroblasts, and dendritic cells. Pyrin appears to act when its phosphorylation is suppressed. This can result when interactions between Rho GTPases and protein phosphokinase interactions are modified following exposure to bacterial toxins.
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 a toxin or infection, resulting in an FMF attack.
●Common MEFV variants – The most common pathogenic variants in individuals with "prototype FMF" (most of whom reside in the Middle East, Turkey, Israel, Iraq, Armenia, and Iran) are in exon 10 (apart from p.E148Q). Exon 10 variants present in 75 percent of these individuals; these include p.M694V, p.M680I, p.M694I, and p.V726A.
•Middle East – The most common variant is p.M694V. Of people in the Middle East who have FMF, 20 to 65 percent carry the p.M694V variant.
•Japan – The most common pathogenic variants occur in exons 1 to 4, accounting for 75 percent of cases. In FMF patients from Japan, the only pathogenic variant in exon 10 is p.M694I.
Individuals who are homozygous for p.M694V or p.M694I tend to have more severe and earlier onset disease and may require higher colchicine doses to prevent attacks. (See 'Implications for patient management' below.)
More than 400 variants have been identified in MEFV. 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 – FMF inheritance is complex. It is usually autosomal recessive (figure 1), meaning biallelic germline pathogenic variants in MEFV (homozygous or compound heterozygous) are required to manifest the disease. Expression is variable, possibly due to other genetic and environmental factors that are hypothesized to exist but are not well understood. (See 'Biallelic pathogenic or likely pathogenic variants' below.)
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, FMF is not purely autosomal recessive since approximately 33 percent of patients are heterozygous for a single pathogenic variant; this represents approximately 2 to 5 percent of heterozygous individuals in endemic countries [3,4]. Common variants in this category include p.M694V, p.M680I, and p.A726V.
In addition, there are rare kindreds where FMF is transmitted as an autosomal dominant trait. This pattern of transmission happens with the following MEFV variants [5-7].
•p.M692del
•p.H478Y
•p.T577N
FMF diagnosis — FMF is a hereditary autoinflammatory disorder characterized by recurrent attacks of fever and serosal inflammation (peritonitis, pleuritis, pericarditis, synovitis) or erysipelas-like erythema. (See "Clinical manifestations and diagnosis of familial Mediterranean fever", section on 'Diagnosis'.)
Progressive secondary (AA) amyloidosis is a devastating complication of FMF that may cause kidney failure and death. Recurrent attacks of peritonitis may cause peritoneal adhesions and small bowel obstruction.
We advise genetic testing for all individuals with suspected FMF if available and feasible. However, some individuals may only have a clinical diagnosis.
●Clinical diagnosis – In endemic countries, a clinical diagnosis of FMF (and the decision to start treatment) is often based on the patient's symptoms and findings, supported by a positive family history (algorithm 1 and table 4). Endemic countries and common variants in those countries are listed above. (See 'MEFV gene' above.)
While the countries in which relatives were born may inform disease prevalence and support clinical diagnosis, country of origin cannot be used to exclude the diagnosis of FMF.
●Definitive diagnosis with genetic testing – Definitive diagnosis of FMF requires genetic confirmation, especially since other autoinflammatory conditions may mimic FMF. (See 'Negative results' below.)
Genetic testing has a particularly significant role in diagnosing FMF in countries where FMF is rare.
Knowledge of the MEFV genotype is also useful for counseling at-risk relatives and to guide the therapeutic approach [8]. Examples are discussed below. (See 'At-risk relatives' below and 'Implications for patient management' below.)
●Support for diagnosis based on response to therapy – In individuals who meet clinical criteria for FMF but, in whom genetic testing is not diagnostic (negative testing, VUS, or heterozygosity for a pathogenic variant in MEFV not known to cause autosomal dominant inheritance), the diagnosis of FMF is supported by a six-month trial of colchicine therapy that results in relief of attacks followed by recurrence of attacks after cessation of treatment [3].
IMPLICATIONS FOR PATIENT MANAGEMENT —
Genetic test results not only confirm the diagnosis of FMF; they may also inform the aggressiveness of therapy. (See 'FMF diagnosis' above.)
Biallelic pathogenic or likely pathogenic variants — We consider all symptomatic patients with biallelic (homozygous or compound heterozygous) germline variants in MEFV that are pathogenic or likely pathogenic to have FMF, regardless of the initial reason for testing and the family history (algorithm 2). Counseling may require additional visits or referral to a genetic counselor or clinical geneticist. (See 'Locating a genetics expert' below.)
Topics of discussion and interventions include:
●Typical triggers and how to minimize them.
•Exaggerated physical stress
•Emotional stress
•Infection
•Cold exposure
•Menstruation
•Missing a dose of colchicine
●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. Individuals with homozygosity for p.M694V are often treated more aggressively (eg, with higher doses of colchicine, possibly using an anti-interleukin 1 agent).
●Options for individuals who cannot tolerate colchicine or whose disease does not respond to colchicine.
●Pregnancy and nursing-specific considerations.
Details and supporting evidence are discussed separately. (See 'UpToDate topics' below.)
Heterozygosity for a pathogenic or likely pathogenic variant — 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 'MEFV gene' above.)
●Heterozygous individuals who meet diagnostic criteria for FMF (table 4) are treated with colchicine similar to those with biallelic pathogenic variants. (See "Management of familial Mediterranean fever", section on 'Initial management with colchicine'.)
●For rare heterozygous FMF patients receiving colchicine who are asymptomatic for more than four to five years and do not display elevated acute phase reactants, it may be possible to discontinue colchicine.
●Heterozygous individuals who do not meet clinical diagnostic criteria can be counseled that they do not have FMF. However, they may develop FMF later in life (algorithm 2). Another option is to use a therapeutic trial of colchicine for further exclusion or confirmation of FMF. (See 'Considerations for relatives' below.)
Variants of uncertain significance (VUS) — Individuals with a VUS should be managed based on their clinical features and family history rather than the VUS (algorithm 2).
New information may become available, and the testing laboratory or other resources should be consulted periodically for updates. (See 'Classification of variants' above.)
Negative results — Negative testing means that no pathogenic or likely pathogenic variants in MEFV were identified. However, some tests only query a subset of variants; pathogenic variants might be present in other parts of the gene and cannot be identified if testing is not comprehensive. 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).
●Approximately 10 to 20 percent of patients who meet clinical diagnostic criteria for FMF do not carry any identifiable pathogenic variants in MEFV [9,10].
In these cases, the diagnosis of FMF is made by a positive colchicine therapeutic trial after excluding other possible diagnoses. The diagnosis of FMF in these cases is considered probable rather than definitive.
●Examples of other genetic conditions in the differential diagnosis of FMF include mevalonate kinase deficiency (MKD) and tumor necrosis factor (TNF) receptor-associated periodic fever syndrome (TRAPS). (See "Amyloidosis: Genetic factors", section on 'Mevalonate kinase deficiency' and "Amyloidosis: Genetic factors", section on 'Tumor necrosis factor receptor-1 associated periodic syndrome'.)
●For individuals with a positive family history of FMF 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 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 variants are not known, genetic testing should first be done on the affected individuals. Referral to a clinical geneticist or genetic counselor may be helpful in determining the optimal testing strategy. (See 'Locating a genetics expert' below.)
CONSIDERATIONS FOR RELATIVES
Reproductive counseling — FMF is generally an autosomal recessive disease, with exceptions listed above. (See 'MEFV gene' above.)
●Children of an affected individual who has biallelic pathogenic variants in MEFV will be obligate carriers of one of the variants.
●Children of an individual who is heterozygous for a pathogenic variant have a 50 percent chance of inheriting the variant. (See 'Heterozygosity for a pathogenic or likely pathogenic variant' above.)
●A child who inherits a pathogenic variant from both parents will have FMF. Additionally, some children may display FMF even with a single pathogenic variant inherited from one parent who may or may not themself have FMF.
●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 a 25 percent chance of not inheriting either pathogenic variant.
At-risk relatives — 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 'Heterozygosity for a pathogenic or likely pathogenic variant' above.)
Relatives at risk for having inherited a pathogenic variant in MEFV should receive information about the importance of genetic counseling and possible testing. We generally wait to test at-risk relatives until they become symptomatic, as some asymptomatic at-risk relatives may remain asymptomatic for life [11]. An exception would be an asymptomatic sibling of an individual with FMF-associated amyloidosis, for whom earlier testing may be appropriate. (See "Clinical manifestations and diagnosis of familial Mediterranean fever", section on 'Secondary (AA) amyloidosis'.)
RESOURCES
UpToDate topics
●FMF:
•Genetics – (See "Familial Mediterranean fever: Epidemiology, genetics, and pathogenesis".)
•Diagnosis – (See "Clinical manifestations and diagnosis of familial Mediterranean fever".)
•Management – (See "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)
