Familial Mediterranean fever: Penetrance of the p.[Met694Val];[Glu148Gln] and p.[Met694Val];[=] genotypes

Eyal, Ori; Shinar, Yael; Pras, Mordechai; Pras, Elon

doi:10.1002/humu.24090

Cited by 14 publications

(7 citation statements)

References 29 publications

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“…34,35 The penetrance of compound heterozygosity of M694V/E148Q was found to be higher than heterozygous M694V, thus implicated in the pathogenesis. 36 However, similar to our results, a recent study showed that compound heterozygosity of M694V with E148Q did not result in a clinically different disease than M694V heterozygotes and suggested as a benign variation. 37 Several inflammatory conditions were shown to be associated with FMF and more frequently detected in the presence of M694V mutation.…”

Section: Discussionsupporting

confidence: 91%

“…In contrast, E148Q was associated with a milder form of FMF in children from Turkey 34,35 . The penetrance of compound heterozygosity of M694V/E148Q was found to be higher than heterozygous M694V, thus implicated in the pathogenesis 36 . However, similar to our results, a recent study showed that compound heterozygosity of M694V with E148Q did not result in a clinically different disease than M694V heterozygotes and suggested as a benign variation 37 …”

Section: Discussionsupporting

confidence: 86%

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Genotype-Phenotype Associations of Children With Familial Mediterranean Fever in a Cohort Consisting of M694V Mutation and Implications for Colchicine-Resistant Disease

2023

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ObjectivesThe aim of this study was to investigate the clinical associations of the second allele mutations and the effect of genotype and presenting features on colchicine resistance in children with familial Mediterranean fever (FMF), carrying at least one M694V variant.MethodsThe medical records of the patients diagnosed with FMF, in whom at least one allele M694V mutation was detected, were reviewed. Patients were grouped according to the genotype as M694V homozygotes, compound heterozygote M694V with an exon 10 mutation, compound heterozygote M694V with a variant of unknown significance (VUS), and M694V heterozygotes. Disease severity was assessed with the International Severity Scoring System for FMF.ResultsAmong the 141 patients included, homozygote M694V (43.3%) was the most frequent MEFV genotype. Clinical manifestations of FMF at diagnosis were not significantly different according to genotypic alterations except homozygote M694V. Besides, homozygous M694V was associated with a more severe disease, with more frequent comorbidities and colchicine-resistant disease. A lower disease severity score was observed in compound heterozygotes with VUS than in M694V heterozygotes (median 1 vs 2, p = 0.006). Regression analysis revealed that homozygous M694V, arthritis, and frequency of attacks were associated with an increased risk of colchicine-resistant disease.ConclusionsClinical manifestations of FMF at diagnosis with a M694V allele were predominantly influenced by the M694V rather than the second allele mutations. Although homozygous M694V was associated with the most severe form, the presence of compound heterozygosity with a VUS did not affect disease severity or clinical features. Homozygous M694V confers the highest risk of colchicine-resistant disease.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 86%

Genotype-Phenotype Associations of Children With Familial Mediterranean Fever in a Cohort Consisting of M694V Mutation and Implications for Colchicine-Resistant Disease

2023

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“…In our study, most patients with NOD2/MEFV variants were heterozygous for MEFV E148Q. Several studies of its pathogenic role in classic FMF were conducted with mixed results ( 35 ), but most literature data have favored its contributory role in autoinflammatory phenotypes that may or may not be classified as typical FMF as is the case with two recent independent Turkish studies ( 36 , 56 ). An Israeli study showed that MEFV E148Q is likely a contributory genetic factor when coinherited with M694V ( 35 ).…”

Section: Discussionmentioning

confidence: 49%

Implications of combined NOD2 and other gene mutations in autoinflammatory diseases

Nomani,

Deng,

Navetta-Modrov

et al. 2023

Front. Immunol.

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NOD-like receptors (NLRs) are intracellular sensors associated with systemic autoinflammatory diseases (SAIDs). We investigated the largest monocentric cohort of patients with adult-onset SAIDs for coinheritance of low frequency and rare mutations in NOD2 and other autoinflammatory genes. Sixty-three patients underwent molecular testing for SAID gene panels after extensive clinical workups. Whole exome sequencing data from the large Atherosclerosis Risk in Communities (ARIC) study of individuals of European-American ancestry were used as control. Of 63 patients, 44 (69.8%) were found to carry combined gene variants in NOD2 and another gene (Group 1), and 19 (30.2%) were carriers only for NOD2 variants (Group 2). The genetic variant combinations in SAID patients were digenic in 66% (NOD2/MEFV, NOD2/NLRP12, NOD2/NLRP3, and NOD2/TNFRSF1A) and oligogenic in 34% of cases. These variant combinations were either absent or significantly less frequent in the control population. By phenotype-genotype correlation, approximately 40% of patients met diagnostic criteria for a specific SAID, and 60% had mixed diagnoses. There were no statistically significant differences in clinical manifestations between the two patient groups except for chest pain. Due to overlapping phenotypes and mixed genotypes, we have suggested a new term, “Mixed NLR-associated Autoinflammatory Disease “, to describe this disease scenario. Gene variant combinations are significant in patients with SAIDs primarily presenting with mixed clinical phenotypes. Our data support the proposition that immunological disease expression is modified by genetic background and environmental exposure. We provide a preliminary framework in diagnosis, management, and interpretation of the clinical scenario.

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“…Observational studies have shown that p.E148Q could potentially increase the effect of moderate alleles such as p.V726A and p.R761H [ 8 , 9 ] . A recent penetrance study in 148 patients referred for FMF found a penetrance 17 times higher for the genotype [(E148Q)];[(M694V)] (p.E148Q and p.M694V in trans ) than [=];[(M694V)] (p.M694V heterozygous) (0.135 and 0.008, respectively) [ 10 ]. Also two recent, independent studies support that p.E148Q could influence the severity of FMF in individuals with a heterozygous B30.2 domain mutation and increase the level of IL-18 cytokine expression at remission in those individuals [ 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

Pyrin variant E148Q potentiates inflammasome activation and the effect of pathogenic mutations in cis

et al. 2023

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Objective The p.E148Q variant in pyrin is present in different populations at a frequency up to 29%, and has been associated with diseases including vasculitis and familial Mediterranean fever (FMF). The pathogenicity of p.E148Q in FMF is unclear, even when observed in cis or in trans to a single, typically recessive, mutation. We performed functional validation to determine whether p.E148Q increases the ability of pyrin to form an active inflammasome complex in cell lines. Methods We interrogated the Australian Autoinflammatory Disease RegistrY (AADRY) to find candidate inheritance patterns for the p.E148Q variant in pyrin. Different pyrin variant combinations were tested in HEK293T cells stably expressing the adaptor protein apoptosis-associated speck-like (ASC) which were analysed by flow cytometry to visualise inflammasome formation, with and without stimulation by Clostridioides difficile toxin B (TcdB). Inflammasome dependent cytokine secretion was also quantified by ELISA of supernatants from THP-1 cells transduced with lentiviral expression vectors. Results In AADRY, we observed the p.E148Q allele in individuals with autoinflammatory diseases alone or in conjunction with other pyrin variants. Two FMF families harbored the allele p.E148Q-M694I in cis with dominant heritability. In vitro, p.E148Q pyrin could spontaneously potentiate inflammasome formation, with increased IL-1β and IL-18 secretion. p.E148Q in cis to classical FMF mutations provided significant potentiation of inflammasome formation. Conclusion The p.E148Q variant in pyrin potentiates inflammasome activation in vitro. In cis, this effect is additive to known pathogenic FMF mutations. In some families, this increased effect could explain why FMF segregates as an apparently dominant disease.

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Familial Mediterranean fever: Penetrance of the p.[Met694Val];[Glu148Gln] and p.[Met694Val];[=] genotypes

Cited by 14 publications

References 29 publications

Genotype-Phenotype Associations of Children With Familial Mediterranean Fever in a Cohort Consisting of M694V Mutation and Implications for Colchicine-Resistant Disease

Genotype-Phenotype Associations of Children With Familial Mediterranean Fever in a Cohort Consisting of M694V Mutation and Implications for Colchicine-Resistant Disease

Implications of combined NOD2 and other gene mutations in autoinflammatory diseases

Pyrin variant E148Q potentiates inflammasome activation and the effect of pathogenic mutations in cis

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