CYSTIC FIBROSIS MUTATION SPECTRUM
IN NORTH MACEDONIA:
A STEP TOWARD PERSONALIZED THERAPY
Terzic M1, Jakimovska M1, Fustik S2, Jakovska T3, Sukarova-Stefanovska E1, Plaseska-Karanfilska D1,*
*Corresponding Author: Professor Dijana Plaseska-Karanfilska, MD, PhD, Research Center for Genetic
Engineering and Biotechnology “Georgi D.Efremov,” Macedonian Academy of Sciences and Arts,
Av. Krste Misirkov 2, 1000 Skopje, Republic of North Macedonia. Tel: +389-23-235-400/264.
E-mail: dijana@manu. edu.mk
page: 35
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RESULTS
In our study, a total of 30 different mutations were
detected in a cohort of 158 unrelated clinically confirmed
CF patients (Table 1).
Allele Frequencies. The most frequent mutation in
our patients was F508del indicating the highest prevalence
of 75.9% (240/316 alleles), followed by G542X
(3.5%; 11/316 alleles), N1303K (1.9%; 6/316 alleles),
CFTR dele2,3 and G1349D (1.6%; 5/316 alleles each).
Two mutations: 621+1G>T and 711+3A>G were found
in four patients each (1.3%; 4/316 alleles). Five mutations
(V456F, G126D, E822X, R347P and 1811+1G>C) were
present with frequencies of 0.95% (3/316 alleles) each.
Eight mutations (R117C, Y161D, 457TAT>G, R1158X,
S466X (TAG), 2789+5G>A, 2184insA and 3849G>A)
were found only in a heterozygous state with frequency
of 0.6% (2/316) separately. A spectrum of eight mutations
(E92X, A357V, E379X, E585X, R1066C, c.2779_2788dup
CTTGCTATGG, 3850-1G>A and 711+1G>T) were
found only once with a frequency of 0.3% (1/316) individually.
The A357V (c.1070C>T; p.Ala357Val) and
c.2779_2788dup CTTGCTATGG (p.Gly930AlafsTer48)
are novel mutations, found for the first time in our cohort.
Both patients also had F508del, but testing parental samples
was available only for the carrier of A357V, where the
trans position of the variants was confirmed. The A357V
(c.1070C>T; p.Ala357Val) mutation was determined in
a male infant with dehydration, vomiting, anorexia and
weight loss, first reported by Fustik et al. [9], where the
clinical symptoms of the patient were described in more detail. The observation of this patient for 2 to 5 years
revealed a mild CF phenotype. Additionally, two large deletions
(CFTRdele11 and CFTRdele4-8) were detected in
a heterozygous state in one patient each (0.3%, 1/316). Respectively,
the most frequent functional class of mutation
was class II (78.8%; 249/316 alleles) with four mutations,
due to the high presence of F508del allele in our cohort.
Following class II, the second most frequent mutation
class is class I (11.1%, 35/316 alleles) with 13 different
mutations. The third most frequent mutation class is class
V (3.8%, 12/316 alleles) with five different mutations, followed
by class III (3.5%, 11/316 alleles) presenting with
four different mutations and class IV (2.8%, 9/316 alleles)
with four different mutations. Mutations belonging to class
VI were not present in our patients. The mutation classes
are presented in Table 1.
Genotype Frequencies. As expected from the allele
frequencies, the most common genotype was F508del/
F508del (57.6%; 91/158) followed by the F508del/non
F508del genotype (36.7%; 58/158) and non F508del/
non F508del (5.7%; 9/158). Following the F508del/non
F508del genotype, most frequent was F508del/G542X
(12.1%; 7/58). From the non F508del/non F508del genotypes,
four included the G542X mutation in combination
with other mutations and the other five genotypes
(621+1G>T/1811+1G>C, E585X/G126D, 2184insA/
CFTRdele2,3, R347P/R347P and 2789+5G>A/2789+5
G>A) were found in one patient each. According to the
mutation classes, the most frequent genotype class was II/
II (63.3%, 100/158), followed by I/II (17.7%; 28/158), II/
III (5.7%; 9/158), II/V (5.1%; 8/158) and II/IV genotype
(3.8%; 6/158). The distribution of CFTR genotypes in our
CF patients is presented in Table 2.
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