Submission Details

Biallelic variants in MEFV were first implicated in autosomal recessive familial Mediterranean fever (FMF) in 1997 (PMIDs:9288094, 9325049). MEFV encodes a pyrin protein (marenostrin) and is involved in innate immunity regulation and inflammatory response (https://www.genecards.org/cgi-bin/carddisp.pl?gene=MEFV). FMF is characterized by recurrent fever, abdominal pain, chest pain, arthralgias, and amyloidosis in some individuals (PMID:20301405). The disorder was originally identified in Mediterranean populations, affecting up to 1 in 500 people in Armenian populations, though individuals with variants in MEFV and features of FMF have also been identified in other populations (PMID:18403822).

Individuals with clinical diagnoses of FMF and heterozygous variants in MEFV have also been reported. These individuals have similar phenotypic severity and age of onset as individuals with biallelic variants in MEFV. In earlier literature, limited genetic testing (such as screening of select exons) was performed and the possibility of a second variant in MEFV undetectable via the methodology used could not be ruled out (PMID:32824452). However, more recent studies performed sequencing of the entire gene as well as haplotype analysis (to identify a common haplotype that might be associated with transmission of a second variant), and also failed to identify a second variant (PMID:19479870). The same variants are observed in heterozygous and homozygous affected individuals as well as heterozygous unaffected individuals. Because of this, the General GCEP has decided to curate this gene-disease relationship using a semi-dominant mode of inheritance.

Variants from 78 probands across 9 publications are included in this curation (PMIDs:9288094, 28483595, 30171907, 11175300, 29543225, 20937419, 34527104, 19479870, 19479871). Variants are predominantly missense, though nonsense, frameshift, and in-frame indel variants have been observed (https://databases.lovd.nl/shared/genes/MEFV). The proposed disease mechanism is gain of function (PMID:21600797). Segregation of MEFV variants with FMF has been documented within numerous families (PMIDs: 20937419, 11977178). Additional genetic evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached.

The gene-disease relationship between FMF and MEFV is also supported by gene-level experimental evidence. Monocytes from clinically affected individuals with FMF showed increased IL-1β secretion compared to clinically unaffected monocytes (PMID:23505242). Monocytes from clinically diagnosed FMF individuals and unaffected individuals in another study were stimulated with proinflammatory mediators, resulting in increased MEFV mRNA in individuals with FMF (PMID:10807793). Additionally there are three homozygous knock-in mouse models of the most commonly observed variants observed in individuals with FMF that show an inflammatory response of differing severities, depending on the variant, further supporting this relationship (PMID:21600797). In summary, there is definitive evidence supporting a gene-disease relationship between variants in MEFV and semi-dominant familial Mediterranean fever. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification has been approved by the ClinGen Gene Curation Expert Panel on 02/23/2022.