FREQUENCIES OF THE MEFV GENE
MUTATIONS IN AZERBAIJAN
Huseynova LS1, Mammadova SN, Aliyeva KAA
*Corresponding Author: Lala S. Huseynova, Ph.D., Department of Medical Biology and Genetics,
Azerbaijan Medical University, Anvar Gasimov Street 14, Baku City AZ1022, Azerbaijan. Tel.: +994-
506-630-623. E-mail: royahuseynova2006@gmail.com
page: 33
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DISCUSSION
To prevent the hereditary disease of FMF, parents
of 42 patients were invited to the consultation of physician-
genetics in 2016-2021. Parents received information
about a healthy child prognosis for the next pregnancy.
When the inheritance type is autosomal-recessive, it has
been reported that the risk of an affected child in the next
pregnancy is 25.0%. As the majority of families are of
reproductive age, they are prepared to consent undergoing
prenatal diagnosis (PND) in future pregnancies.
The following mutations of the MEFV gene have
been identified in Turkey: E148Q, R202Q, P369S, F479L,
M680GA, M680GC, M694V, M694I, K695R, V726A,
A744S and R761H [11]. In the diagnostics of the disease,
great significance is given to who are the ancestors of the
patient and to which ethnic group they belong [10].
Fragouli et al. [15] studied FMF in native Cretans,
analyzing the 12 most frequent MEFV mutations in 71 patients
and 158 healthy controls, and found that 59 (83.1%)
of 71 FMF patients had at least one MEFV mutation, with
five homozygotes and 54 heterozygotes; no mutations were
detected in 16.9% of patients. Population genetic analysis
showed an FMF carrier frequency in the healthy Cretan
population of approximately 1:17 or about 6.0%. They
noted that this placed the Cretan population in the ‘high
risk’ category in terms of FMF prevalence [15].
By mutational analysis of 376 Lebanese patients with
FMF, Jalkh et al. [16] found that the most common mutations
were: M694V (28.98%), M694I (12.10%), V726A
(19.28%), M680I (5.72%) and E148Q (10.10%), respectively.
These mutations were estimated to be 7000, 8500,
15,000, 23,000, and 30,000 years old, respectively. Varying
the mutation rate at one of the haplotype markers led to
younger age estimates ranging from 3625 to 18,650 years.
A total of 333 different haplotypes were found, 31 of which
had a frequency greater than 5.0% in the whole sample.
A comparison of haplotype distributions among religious
groups showed that Muslim sub populations including
Shiites and Sunnites, as well as Christians and Armenians
[who were formerly settled in the southeastern part of
Asia Minor (Cilicia)], were all descendants of an ancient
common ancestral population, in which most of the MEFV
mutations were already present with their respective associated
haplotypes [16].
Bonyadi et al. [17] tested for five common mutations
on the MEFV gene (E148Q, M680I, M694V, M694I, and
V726A) in 524 unrelated Iranian patients of Azeri Turkish
origin with FMF, and found their overall frequency to
be 52.0%. Further analysis of 10 less common mutations
enabled detection of approximately 9.0% of the unidentified
alleles. The R761H mutation was the most frequently found
of the rare alleles (4.7%), and the authors suggested that
R761H should be included in routine molecular diagnosis of
FMF patients from this ethnic group. Five different complex
alleles were identified in 14 patients, including homozygosity
for E167D/F479L in two patients. They noted that
43.0% of presumably mutated alleles remained elusive [17].
Otsuka et al. [18] reported a 32-year-old Japanese
man with adult-onset fever, tonsillitis, and skin rash associated
with leukocytosis, increased C-reactive protein,
increased ferritin, and activation of monocytes. His rash
consisted of painless papules and plaques. Skin biopsy
showed neutrophilic dermatosis, and he was diagnosed
clinically with adult-onset Sweet disease. He showed a
favorable response to colchicine and low-dose corticosteroids. Genetic analysis identified a heterozygous E148Q
variant in the MEFV gene, which the authors noted is
found in about 20.0% of healthy individuals in Japan.
Functional studies of the variant were not performed, but
they suggested that the variant may have contributed to
the development of the disorder [18].
Berg et al. [19] reclassified the R408Q mutation as
‘considered to imply carrier status’ for a recessive disorder.
They noted that the R408Q and P369S mutations had
been reported in cis as a single allele resulting in a highly
variable clinical phenotype [19].
Masters et al. [20] noted that the molecular mechanism
resulting from the S242R mutation differed from
that of FMF-associated mutations M694V, M680I, and
V726A, which had no appreciable effect on 14-3-3 binding.
Of note, the carrier’s mother in Family C did not have
neutrophilic dermatosis, but she did have some features
of the disorder, including recurrent fevers and elevated
acute-phase reactants. These findings suggested incomplete
penetrance or clinical variability [20].
Kiyota et al. [21] reported a 45-year-old Japanese
man with a systemic autoinflammatory disorder with
intermittent fever and amyloidosis, consistent with FMF,
as well as pustular dermatosis with neutrophilic aggregates
since childhood. The authors noted that he had
abdominal symptoms, rather than classic serositis, and
that the skin problems had been the main symptom since
childhood, suggesting a phenotype that overlapped with.
Genetic analysis identified compound heterozygous missense
variants in the MEFV gene (S242R and E148Q,
His unaffected mother was heterozygous for the S242R
mutation, indicating incomplete penetrance of acute febrile
neutrophilic derma-tosis (AFND). Functional studies
of the variants were not performed, but the authors
suggested that the E148Q polymorphism may act as a
disease modifier [21].
In three affected members of a Spanish family with
acute febrile neutrophilic dermatosis, Moghaddas et al.
[22] identified a heterozygous c.730G>A transition in exon
2 of the MEFV gene, resulting in an E244K substitution
at a highly conserved residue. The mutation, which was
found by direct sequencing of exon 2 of the MEFV gene,
was not found in the 1000 Genomes Project, ExAC, or Exome
Variant Server databases (https://reseaarch.monash.
eud/en/publications/a-novel-pyrin-associated-autoinflam
mation-with-neutrophilic-derma) or in 250 healthy Spanish
controls [22].
Grossman et al. [23] reported a comprehensive characterization
of the phenotypes of 57 patients with FMF
who were homozygous for the M694V mutation on the
MEFV gene compared to the phenotypes of a cohort of 56
patients with FMF and other MEFV genotypes. They found
that disease severity and average frequency of attacks per
year, both before and after treatment, were higher in the
M694V homozygous group compared to the cohort of
patients with other MEFV genotypes, although there was
no difference in the length of attacks or in the proportion
of patients with abdominal, erysipelas-like erythema and
fever-alone attacks. They also found that the colchicine
dose was higher and the response to colchicine was lower
in the homozygous M694V cohort. Additionally, the homozygous
cohort had a higher overall rate of diseases
associated with FMF, including Crohn’s disease, Behçet
disease, ankylosing spondylitis and Henoch Schonlein
purpura, but not fibromyalgia [23].
Several reports have shown that the M694V mutation
is associated with severe disease featuring early onset,
high frequency of attacks, the need for the high doses of
colchicine and high frequency of amyloidosis in untreated
patients [24-26].
The high frequency of MEFV mutations in the four
classically affected populations, ranging from 37.0 to
39.0% in Armenians and Iraqi Jews, to 20.0% in Turks,
North Africans and Ashkenazi Jews and Arabs [11]. All
molecular genetic methods for detecting mutations are
based on differences in the DNA sequence.
We identified seven previously known mutations of
the MEFV gene: R761H, M694I, M694V, V726A, R202Q,
M680I and E148Q for the population of Azerbaijan. Two
mutations, E148Q and R202Q, are located in the exon 2,
the remaining five mutations, R761H, M694I, M694V,
V726A, and M680I, in the exon 10 of the gene. In order
to prevent periodic illness in families with a genetic risk of
having a sick child, PND of the fetus in the first trimester
of pregnancy is planned, using a molecular genetic method
of research. (Table 1).
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