CYSTIC FIBROSIS IN MACEDONIA: AN UPDATE
Koceva S1,2, Plaseska-Karanfilska D1, Fustic-Naceva S2, Caparevska M3, Efremov GD1
*Corresponding Author: Professor Dr. Georgi D. Efremov, Macedonian Academy of Sciences and Arts, Research Center for Genetic Engineering and Biotechnology, Av. Krste Misirkov 2, POB 428, 1000 Skopje, Republic of Macedonia; Tel: +389 2 239 061; Fax: +389 2 115 434; E-mail: gde@manu.edu.mk
page: 47

RESULTS

Since the beginning of the program for molecular characterization of CF in Macedonia in 1989, a total of 228 unrelated patients suspected for the disease were referred for genetic testing to the laboratory of the RCGEB, MASA, Skopje, Republic of Macedonia. The main indications for referral were chronic pulmonaly disease and initial positive sweat test. Over the years, 107 patients were excluded from the CF registry, and from the program for detailed molecular analysis because of the lack of a positive sweat test on three consecutive tests, and of the disappearance of symptoms with advanced age of the patients.

      Table 1 summarizes the results on the frequencies of different CFTR gene mutations found in 121 patients who remained in the CF Registry in the Republic of Macedonia. A total of 13 different mutations were detected, the most frequent being DF508 (62.4%), followed by G542X (5.3%), N1303K (2.2%) CFTRdele21kb (1.6%), 621+1G?T (1.3%), 711+3AG (0.9%), 3849GA (0.9%), 457TATG (0.9%), V1397E (0.9%), 2184insA (0.9%) 1811+1GC (0.4%), 2789+5GA (0.4%), and Y569C (0.4%). Four of the mutations (711+3AG, 1811+1GC, V1397E and Y569C) were described for the first time [21-24]. The DF508 mutation showed a higher incidence among Macedonians (67.8%) than among Albanians (58.1%) living in Republic of Macedonia (Table 2). The observed difference does not reach statistical significance. During this study eight known (R75Q, 405+46G/T, 875+40A/G, L467P, M470V, T966T, 3041-92G/A and 4002A/G), and one new (P324P) polymorphism in the CFTR gene were found [25].

      Thirty-one prenatal diagnoses were performed in 31 families at-risk for a child with CF (Table 3). In eight fetuses the analysis showed absence of mutation on both chromosomes, 17 fetuses were carriers, while six fetuses were affected with CF. In all instances the results were confirmed after birth or after termination of pregnancy.

 

 Table 1. Frequency of different CF mutations identified in patients from the Republic of Macedonia

 

Mutations

Nucleotide

Exon/Intron

Type of Mutation

Number (%) of CF Chromosomes

DF508

3 bp del. 1652/1655

10

deletion

151 (62.4)

G542X

G>T at 1756

11

nonsense

  13 (5.3)

N1303K

C>G at 4041

21

missense

    5 (2.2)

621+1G>T

G>T at 621+1

  4

splicing

    3 (1.3)

CFTRdel21kb

del. exons 2+3

2-3

deletion

    4 (1.6)

2184insA

ins. At 2184

13

insertion

    2 (0.9)

457TAT>G

TAT>G at 457

  4

frameshift

    2 (0.9)

711+3A>G

A>G at 711+3

  5

splicing

    2 (0.9)

V1397E

T>A at 4322

23

missense

    2 (0.9)

3849G>A

G>A at 3849

19

splicing

    2 (0.9)

Y569C

A>G at 1838

12

missense

    1 (0.4)

1811+1G>C

G>C at 1811+1

11

splicing

    1 (0.4)

2789+5G>A

G>A at 2789+5

14b

splicing

    1 (0.4)

TOTAL

 

 

 

189 (78.0)




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