Increasing Importance of Genotype-Phenotype Correlations Associated with Common and Rare MEFV Gene Mutations in FMF
Sema Yildirim1, Hayrunnisa Bekis Bozkurt2, Muferet Erguven3
1Department of Pediatrics, Göztepe Prof. Dr. Süleyman Yalçın City Hospital, 34722 İstanbul, Turkey.
Abstract:
Background/Objectives: Studies have shown that some mutations, especially M694V, are correlated with renal RI and/or AA. There are limited data about rare mutations on severity of the disease and RI. Today, evaluating genotype-phenotype correlations in rare mutations is important to better understand FMF. We aimed to evaluate clinical, demographic and genetic changes and genotype-phenotype correlations in pediatric patients with FMF over thirty years as well as the importance of the rare mutations. Methods: A total of 2765 pediatric patients with FMF were included in this study. Genetic results were firstly divided into ten groups including rare mutations. Rare mutations were seen in 2% of all patients and divided into eight groups. Results: There was a significant increase in compound heterozygous mutations, E148Q het/hom, R202Q het/hom, complex mutations and rare mutations in the last decade. RI wo AA was 5.8% and AA was 1% in the patients with rare mutations. While M694V and compound het with M694V were positively correlated with severe PRAS, E148Q and V726A were negatively correlated with severe PRAS (p < 0.05, R = 0.137, R = -0.077, R= -0.05, respectively). Although K695R mutation was negatively correlated with severe PRAS (p < 0.05, R = -0.04), the rate of RI was 20%. Although the rare mutation R761H was negatively correlated with severe PRAS (p < 0.05, R = -0.051), the colchicine resistance rate was 8.3%. Conclusions: It may be misleading for clinicians that mutations which have increased in frequency over the years are clinically mild. RI and AA rates in rare mutations are not less than the related rates in common mutations.
Insights
Rare mutations in Familial Mediterranean Fever (FMF) are not milder than common mutations, showing similar rates of renal involvement and amyloidosis. Clinicians should not assume increased mutation frequency indicates milder disease in FMF patients.
Area of Science:
- Genetics and Molecular Biology
- Rheumatology
- Pediatric Medicine
Background:
- Familial Mediterranean Fever (FMF) is a genetic autoinflammatory disorder.
- Common mutations like M694V are linked to disease severity, but data on rare mutations is limited.
- Understanding genotype-phenotype correlations, especially for rare mutations, is crucial for FMF management.
Purpose of the Study:
- To evaluate clinical, demographic, and genetic trends in pediatric FMF patients over 30 years.
- To analyze genotype-phenotype correlations, focusing on the impact of rare mutations.
- To assess the significance of rare mutations in FMF severity and outcomes.
Main Methods:
- Retrospective analysis of 2765 pediatric FMF patients.
- Genetic data categorized into ten groups, including eight distinct rare mutation groups.
- Statistical analysis to determine correlations between genotypes and clinical phenotypes.
Main Results:
- A rise in compound heterozygous, E148Q, R202Q, complex, and rare mutations observed in the last decade.
- Rare mutations showed a 5.8% rate of renal involvement without amyloidosis and 1% rate of amyloidosis.
- Specific mutations showed varied correlations with severe disease, with some rare mutations exhibiting significant renal involvement rates.
Conclusions:
- Mutations increasing in frequency may not necessarily be clinically mild.
- Rare FMF mutations demonstrate renal involvement and amyloidosis rates comparable to common mutations.
- Comprehensive genetic evaluation is essential for accurate FMF prognosis and management.
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