Evaluation of the Clinical Effects and Frequency of MEFV Gene Mutation in Patients with Inflammatory Bowel Disease

Şahin, Seda; Güleç, Derya; Günay, Süleyman; Çekiç, Cem

doi:10.1155/2021/5538150

Cited by 6 publications

(6 citation statements)

References 19 publications

(21 reference statements)

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“…Therefore, in view of the frequent occurrence of FMF in the population at risk, several authors have called for the inclusion of genetic screening for FMF in the investigation of IBD children of Mediterranean ancestry who display unexplained recurrent isolated fever or other atypical FMF manifestations (repeated tonsilitis in early childhood and isolated arthralgia/myalgia, etc.) ( 20 , 40 ).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, some authors suggest that the environment also affects the phenotype of a monogenic disease of the innate inflammatory pathway ( 44 ). The concomitant presence of MEFV mutations in diseases other than FMF may modify their presence and severity ( 20 , 36 , 40 , 43 ). Particularly, recent studies have revealed an increasing spectrum of rare monogenetic diseases, which can present with IBD or IBD-like intestinal inflammation, particularly with VEO IBD.…”

Section: Discussionmentioning

confidence: 99%

“…There are reports on the concurrent occurrence of FMF and IBD. As known, the level of awareness of FMF is far from being sufficient, and it is assumed that there may be many patients with FMF who are under observation without an accurate diagnosis (17)(18)(19)(20). The possibility of developing intestinal vasculitis in FMF is also suggested (21,22).…”

Section: Introductionmentioning

confidence: 99%

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Familial Mediterranean fever in Armenian children with inflammatory bowel disease

Amaryan,

Sarkisian,

Tadevosyan

et al. 2024

Front. Pediatr.

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Inflammatory bowel disease (IBD) and familial Mediterranean fever (FMF) are inflammatory diseases with complex interactions among genetic, immune, and environmental factors. FMF is a monogenic autoinflammatory disease, characterized by recurrent febrile attacks and polyserositis, and is manifested mainly in childhood. FMF is widespread in Armenia. There are reports on the concurrent occurrence of FMF and IBD. MEFV gene mutations may have a disease-modifying effect on IBD. We have investigated the frequency of MEFV mutations and FMF in Armenian children with IBD and their influence on the clinical course. A total of 69 untreated IBD patients under 18 years of age were enrolled: 52.1% (36) had ulcerative colitis (UC), 21.7% (15) had Crohn's disease (CD), and 26.0% (18) had unclassified colitis (IBD-U). The frequency of FMF among them was 36.2% (25/69), and MEFV mutations were identified in 53.6% (37/69). The highest rate of MEFV mutations and FMF was in UC patients (61.1% and 41.6% respectively). In all, 56.7% (21/37) of IBD patients with MEFV mutations had M694V mutated alleles, mainly in compound heterozygous and heterozygous states. There were no associations in the group of IBD patients with coexisting FMF (25), either between any MEFV mutation and type of IBD or coexistence of FMF. Overall, 36.0% (9/25) of them developed VEO IBD and carried mainly the M694V mutation. We concluded that the carrier frequency of MEFV mutations among Armenian pediatric IBD patients was rather high (53.6%), especially for UC. It was suggested that the MEFV gene is not necessarily a susceptibility gene but most likely modifies the course of IBD. MEFV genetic testing was recommended for Armenian pediatric IBD patients, especially for VEO UC and IBD-U, atypical IBD course, or resistance to the conventional treatment. They should also be asked for isolated febrile attacks, recurrent arthritis, and family history, even in the absence of FMF typical symptoms, to rule out FMF and its complications.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Familial Mediterranean fever in Armenian children with inflammatory bowel disease

Amaryan,

Sarkisian,

Tadevosyan

et al. 2024

Front. Pediatr.

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“…Most pathogenic MEFV variants are missense substitutions leading to inappropriately elevated or prolonged inflammatory responses, though controversy remains over pathogenicity criteria [76][77][78]. Many studies have proposed a link between MEFV variants and GI inflammation [79][80][81][82][83][84][85][86] -with some identifying FMF patients presenting with GI phenotypes "mistaken" for IBD [87][88][89][90][91][92] and others reporting MEFV variants that may influence risk or contribute to IBD pathogenesis [93][94][95][96][97]. A recent systematic review and meta-analysis found that MEFV mutated alleles were more frequently found in IBD patients vs controls, with Exon 10 variants (like our patient's) having the most severe impact [98].…”

Section: Families Without Definitive Diagnosesmentioning

confidence: 99%

A Next Generation Sequencing (NGS)-based approach to diagnosing Algerian patients with suspected Inborn Errors of Immunity (IEIs)

Peng

Al-Ddafari²,

Caballero-Oteyza³

et al. 2023

Preprint

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The advent of next-generation sequencing (NGS) technologies has greatly expanded our understanding of both the clinical spectra and genetic landscape of inborn errors of immunity (IEIs). As history has shown and recent large-scale studies of monogenic risk for severe COVID have confirmed, endogamous populations may be enriched for unique, ancestry-specific disease-causing variants as a consequence of geography and/or culture. From a diagnostic perspective, this consideration may significantly impact molecular testing and analysis strategies. Herein, we report on the diagnostic yield of a 2-step NGS-based testing approach beginning with targeted gene panels (TGPs) and reflexing to whole exome sequencing (WES) if negative for Northwest Algerian patients with suspected IEIs. A total of fourteen families were screened using TGPs tailored to their IEI subtypes of common variable immunodeficiency (CVID), inflammatory bowel disease (IBD) or chronic mucocutaneous candidiasis (CMC)-hyperIgE syndrome (HIES), resulting in a total of four definitive or highly likely molecular diagnoses (29% yield). Subsequent application of WES to eight of the ten remaining unsolved cases yielded an additional four diagnoses, giving a 57% overall yield. At least two additional individuals were found to harbor suggestive candidate variants on exome warranting further investigation, while others carried candidate variants or known risk alleles likely contributing to their clinical findings. Only in one patient’s case did we fail to identify any viable potential candidates. By achieving diagnostic yields comparable to those currently quoted for application of short-read NGS to IEI detection, our study demonstrates the viability of a 2-step NGS-based testing strategy in a selected endogamous population. Data from our localized cohort also showed some similarities and differences from NGS studies performed on larger regional IEI cohorts. Finally, our results also highlight many short-comings currently inherent to the application of genomics for clinical IEI diagnostics. Not only does the global community need to address ongoing inequities in representation, access, and infrastructure, but the ability to obtain precise and detailed clinical data remains paramount for achieving diagnostic certainty in the face of complex genotype-phenotype relationships.

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“…Patient cohorts have also shown that FMF mutation carriers could be predisposed to other inflammatory diseases independently of FMF [ 14 ]. p.E148Q specifically has been associated with IgA vasculitis [ 15 , 16 ], Ulcerative Colitis and the need for surgery [ 17 ], Crohn’s disease and perianal injury [ 18 ], a stricturing disease pattern, and extra-intestinal disease [ 19 ]. It has also been shown to increase the risk of developing AA amyloidosis alone or in combination with other autoinflammatory diseases (AID) causing mutations [ 20 ].…”

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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Evaluation of the Clinical Effects and Frequency of MEFV Gene Mutation in Patients with Inflammatory Bowel Disease

Cited by 6 publications

References 19 publications

Familial Mediterranean fever in Armenian children with inflammatory bowel disease

Familial Mediterranean fever in Armenian children with inflammatory bowel disease

A Next Generation Sequencing (NGS)-based approach to diagnosing Algerian patients with suspected Inborn Errors of Immunity (IEIs)

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

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