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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DISCUSSION
The molecular characterization of CF in the Republic
of North Macedonia was initiated in 1989, shortly after
the identification of the CFTR gene. Until 1990, a total of
19 unrelated families from the southern part of Yugoslavia
were analyzed at the Research Center for Genetic Engineering
and Biotechnology “Georgi D. Efremov”, Macedonian
Academy of Sciences and Arts, Skopje, Republic
of North Macedonia, showing a very low distribution of
the F508del mutation (39.5%) [10]. In the following few
years, more CF families were examined, but the frequency
of the F508del mutation remained low (47.9%) [11]. In
2001, a reevaluation of the clinical features of the CF
patients from the CF registry was performed and resulted
with increasing the overall distribution of the F508del
mutation to 62.4%, close to distributions observed in other
Southeast European populations and neighboring regions.
In this study, we present the results of the comprehensive
genotyping of 158 CF patients, including the distribution
of mutation classes in our country. The F508del mutation
still remains the most common mutation in our cohort,
being present in 75.9% of the analyzed alleles (143/194
Macedonian alleles; 73.7%, 94/118 Albanian alleles; 79.7%
and 3/4 other alleles 75.0%). This is similar to the frequency
reported in Serbia and Montenegro (72.28%) [12] and correlates
with most of the European populations. Among the
other countries in the Balkan region, a lower frequency
of F508del was reported (Albania 69.9%, Greece 53.4%,
Bulgaria 62%) [12-14]. The second most frequent mutation
was G542X found in 3.5% of our patients, similar to the frequencies reported in our neighboring countries (Bulgaria
4.2%, Greece 3.9%, Serbia and Montenegro 2.57%). This
mutation is most commonly found in the Mediterranean
regions of Europe and Africa. However, several mutations
that were found more than once in our group of patients,
have not been mentioned in the studies of the neighboring
countries: G1349D, V456F, G126D and R117C.
Accordingly, the genotype F508del/F508del is the
most frequently found in all ethnic cohorts analyzed in
our group of CF patients with a distribution of 57.6%. The
F508del/G542X and F508del/N1303K genotypes, which
are most frequent after F508del/F508del, were found in
four patients from the Macedonian cohort and in three
patients from the Albanian cohort; and in five patients
from the Macedonian cohort and in one patient from the
Albanian cohort, respectively. Two mutations that were
found in a homozygous state (R347P/R347P and 2789+5
G>A/2789+5G>A) were exclusive to two Albanian patients,
while the F508del/621+1G>T genotype was the
only F508del/non F508del genotype represented in all of
the three different cohorts.
To date, molecular characterization of the CF patients
leads toward personalized therapy as the best proposed
therapy for class I mutations, which cause premature termination
codons (PTC), include the aminoglycosides that
are active against PTCs. Also, other formulas, such as
ELX-02, are in ongoing clinical trials evaluating the effect
on class I mutations. Unfortunately, so far no single drug
is able to accomplish the complete rescue of the CFTRF508del
protein that is carried by 94.3% (149/158) of
our patients. Recently, the combined use of potentiator
and corrector molecules, verified to be beneficial for the
homozygous F508del patients, have been approved by
the US Food and Drug Administration (FDA) and by the
European Medicines Agency (EMA) [15]. Likewise, since
2012, the use of a small molecule acting as potentiator,
called ivacaftor, upgraded the treatment of patients with
CF, stabilizing the open gate state and by that increasing
the chloride transport by the mutant type CFTR protein
up to 50.0%. This treatment corresponds to class III mutations
(G1349D) but is also beneficial for several class IV
(R117C) and class V mutations (711+3A>G and 2789+5
G>A) that are present in 7.6% (12/158) of our patients’
genotypes. The comprehensive molecular characterization
of CF in our country identified the patients that would
benefit from a novel targeted therapy. At the present time,
the treatment would be most beneficial for 16 patients who
have mutations belonging to class III, plus the mentioned
mutations from other classes (R117C, 711+3A>G and
2789+5G>A). The knowledge of CFTR mutation classes
in our CF patients represents a first step toward personalized
therapy for CF in our country.
Moreover, determining the spectrum of mutations
in the registered CF patients is leading toward adjusting
the first line screening protocol for the most common
mutations in our population. Comparison between
various commercial kits for detection of CF mutations
was also performed. We concluded that the available kits
(INNO LiPA CFTR (19 and 17+Tn) cover 86.0% of the
mutations found in our patients. Elucigene kits: CF30v2,
CFEU2v1,CF DE and CF ITALIA (same as the CF UK
panel) cover: 84.0, 87.0, 85.0 and 0.63%, respectively, of
the mutations detected in our cohorts and ViennaLab kits:
CF, CF TUR and CF GER cover: 86.0, 85.0 and 86.0%,
respectively, of our patients’ mutations. This raised the
need to design method with another panel of mutations,
more appropriate and accurate for our population. The
previously introduced SNaPshot method published by
Noveski et al. [8], was modified with introduction of
the recurrent mutations determined in our cohort of CF
patients to include 11 different CFTR mutations (F508del,
G542X, N1303K, 621+1 G>T, 2184insA, V456F, G126D,
G1349D, E822X, 711+3 A>G, R117C). With this approach,
we are covering ca. 90.0% of the mutations found
in our population. This makes the modified screening
method more cost-effective and with a better detection rate
in our population compared with the available commercial
kits. To date, CF mutation detection is not a first line
method in newborn screening of CF in our country. This
kind of well-adjusted protocol facilitates faster genotyping
of suspected CF individuals, giving the definite diagnosis
and possibility to adjust treatment and to prolong the
life expectancy of the CF individual. Furthermore, using
this approach we would also have an effective first-line
screening of the newborns.
Declaration of Interest. The authors report no conflicts
of interest. The authors alone are responsible for the
content and writing of this article.
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