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Geno-phenotypical Correlations in Italian People Afflicted with Familial Mediterranean Fever (FMF)
Claudia Cerquaglia1, Micaela La Regina1, Marialuisa Diaco1, Ferruccio D'Onofrio1, Grazia Pomponi2, Giovanni Neri2, Grazia Maria Marino2, Alessandra Terracciano2, Isabelle Touitou3, Giovanni Gasbarrini1, and Raffaele Manna1
1Periodic Fevers Research Centre, Department of Internal Medicine, Catholic University of Sacred Heart, Rome, Italy;
2Institute of Human Genetic, Catholic University of Sacred Heart, Rome, Italy;
3Laboratory of Genetic, A. Villeneuve Hospital, Montpellier, France
In the registry of our Centre of Periodic Fevers 146 adult patients with FMF are recorded; according to Tel-Hashomer criteria, 122 patients had a diagnosis of certain FMF and 22 probable.
Complete MEFV sequencing was performed in 144 Italians with FMF diagnosis; 2 patients refused to perform genetic test.
From genetic test 54/144 (37,5%) patients had two MEFV mutation, 31/144 (21,5%) patients had least one MEFV mutation, 46/144 (32%) patients had not any known MEFV mutation. We found 10/144 (6,9%) patients with R202Q in heterozygosis and 6/144 (4,2%) patients with R202Q in associations with other MEFV mutations.
M694V, in heterozygosis or homozygosis, was the most frequent mutation (41%), followed by M680I (21%), M694I (20%), E148Q (19%), V726A (13%), R761H (7%) and M680I G>A (5%). The prevalence of M694I, a mutation frequently encountered in Maghrebins, and of the rare form of M680I (M680I G>A) was relatively high in Italians (20% and 5% respectively). Other rare exon 10 mutations were also found: A744S, S675N, C280A, E167D, P369S, R408Q, K695R, I369S, P369Q and a stop codon mutation Y688X. No complex allele was detected.
The results of geno-phenotypical correlations are: 1. homozygotes for M694V and M694I are associated with more severe phenotype (mean severity score 9 and 8,6 respectively) than heterozygotes at these codons (mean severity score 7.1 and 6,2 respectively); 2. homozygotes and heterozygotes at codons 680 are associated with a moderate phenotype (mean severity score 7.5); 3. homozygotes at codons 148 show a little more mild phenotype (mean severity score 5) than heterozygotes (mean severity score 6,9); 4. patients with only R202Q or with this polymorphism in association with in other mutations show moderate phenotype (mean severity score 6,4 and 7,6 respectively); 5. patients with other mutations in heterozygosis or homozygosis are not a phenotypically homogeneous group, with a severity score ranging from 2 to 13; 6. patients without any known mutation show moderate phenotype (mean severity score 7).
In conclusion, Italians with FMF show a moderate phenotype independently from the genotype, probably due to the modulator effect of other genes. Really, 55,5% of our patients have moderate phenotype, 28,8% mild and only 15,7% severe. We would point out 32% patients with severe phenotype have M694V and 32% (among them 3 cases of renal amyloidosis) does not have any known mutation, renforcing the idea that probably other genes play a role: investigations by microarrays are currently ongoing.
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