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

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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