THE MEFV GENE PATHOGENIC VARIANTS
AND PHENOTYPE-GENOTYPE CORRELATION
IN CHILDREN WITH FAMILIAL MEDITERRANEAN FEVER
IN THE ÇANAKKALE POPULATION
Battal F, Silan F, Topaloğlu N, Aylanç H, Yıldırım Ş,
Köksal Binnetoğlu F1, Tekin M1, Kaymaz N1, Ozdemir O,
*Corresponding Author: Assistant Professor Dr. Şule Yıldırım, Department of Pediatrics, Faculty of Medicine, Çanakkale
Onsekiz Mart University, Terzioğlu Yerleşkesi Ek Bina, 17100, Çanakkale, Turkey. Tel: +90-286-2180018/2107. Fax: +90-
286-263-59-56. E-mail: sule.yildirim@comu.edu.tr
page: 23
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RESULTS
The cohort was composed of 60 FMF children with
mean ages of 10.48 ± 4.83 (3-18 years), and a 28 male
(46.7%) to 32 female (53.3%) ratio of 1:1.14. Various
combinations and point pathogenic variants were detected
in all patients. Forty-six (70.0%) were heterozygous, six
(10.0%) were homozygous and 12 (20.0%) were compound
pathogenic variant profiles (Table 1). The genetic
analysis of the current 60 mutated FMF children revealed
that p.Met694Val was the most frequent pathogenic variant,
followed by p.Glu148Gln, p.Met6801le, p.Arg202Gln,
p.Val726Ala, p.Pro369Ser and p.Lys695Arg (Table 2).
The main clinical features of the patients were as
follows: parental consanguinity was detected in eight
(13.3%), appendectomy was detected in four (6.7%),
abdominal pain was observed in 32 (53.3%), colchicine therapy in 48 (80%), fever in 14 (23.3%), arthritis in 14
(23.3%) and erysipelas-like erythema in three (5.0%). The
detected pathogenic variants were mainly located at codons
p.Met694Val, p.Glu148Gln, p.Met6801le, p.Arg202Gln,
p.Val726Ala, p.Pro369Ser and p.Lys695Arg. The most
common pathogenic variant was the p.Met694Val heterozygote
(20.0%), followed by the p.Glu148Gln heterozygote
(13.3%). The p.Met680Ile, p.Arg202Gln, p.Val726
Ala, p.Pro369Ser and p.Lys695Arg pathogenic variants
were 11.7, 11.7, 6.7, 5.0 and 5.0%, respectively.
Table 2 shows the pathogenic variant prevalence as a
function of the clinical characteristics in the current FMF
cohort. The compound pathogenic variants of p.Met680
Leu and p.Glu148Gln were frequently found in 14.3%
of the fever cases. Notably, both the p.Met694Val and
p.Met694Ile pathogenic variants were found in 6.3% of the
abdominal pain group, and in 7.1% of the arthritis group
(Table 2). Phenotype severity was evaluated according
to the subsequent genotype (11) in 60 patients (Table 2).
No difference was found when FMF patients carrying
two mutated alleles (homozygous or compound heterozygous)
were compared with those carrying only one
mutated allele (heterozygous) (p >0.05). Two heterozygous
pathogenic variants at codon p.Arg202Gln, one at codon
p.Lys695 Arg and one compound heterozygous pathogenic
variant at codons p.Met680Ile/p.Met694Ile were detected
in children with evidence of an appendectomy. Two heterozygous
pathogenic variants at codon p.Met694Val and
one at codon p.Pro369Ser were detected in three children
with erythema.
Genotype results for 32 children (53.4%) with abdominal
pain showed: two homozygotes for p.Met694Val,
two homozygotes for p.Met680Ile and 20 heterozygotes for
the p.Met694Val, p.Glu148Gln, p.Met680Ile, p.Val726Ala
and p.Arg761His codons, and five compound heterozygotes
for the codons p.Met680Ile/p.Met694Val, p.Met680
Leu/p.Glu148Gln, p.Val726Ala/p.Arg202Gln and p.Pro
369Ser/p.Glu148Gln (Table 2).
Ten children with fever showed heterozygous pathogenic
variants for p.Met694Val (three patients), p.Metl80
Ile (one patient), p.Arg202Gln (three patients), p.Pro369
Ser (two patients) and IL-28β (one patient). Four children with fever showed compound heterozygous pathogenic
variants for codons p.Met680Leu/Pro, p.Glu148Gln and
p.Val726Ala/p.Arg202Gln (Table 2).
One compound heterozygous pathogenic variant at
codons p.Met694Val/p.Met680Ile, one homozygous pathogenic
variant at codon p.Met694Val and 12 heterozygous
pathogenic variants at codons p.Met694Val, p.Met680Ile,
p.Lys695Arg, p.Glu148Gln, p.Arg202Gln, p.Pro396Ser
were detected in children with arthritis. Forty-eight FMF
children (80.0%) were treated with colchicine (1-2 mg/
per day). One patient was unresponsive to the colchicine
therapy (Table 1).
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