Cystic Fibrosis Mutations in Turkey

1. Cystic Fibrosis Mutations in Turkey Prof. Dr. Deniz Doğru Ersöz Hacettepe University Faculty of Medicine Pediatric Pulmonary Medicine Unit

2. Genetics of CF • The gene for CF is localized to the long arm of chromosome 7 • Over 1500 mutations in this gene have been described so far (1604)

3. CF Gene CF gene codes for a protein of 1480 amino acids , called “CF transmembrane regulator(CFTR) protein”

4. CFTR

5. CFTR mutations Severe Mild

6. Cystic Fibrosis in Turkey • 24 centers and 70 doctors are involved • CF birth prevalance: 1/3000 • It is estimated that there are 5000 underdiagnosed CF patients • A national registry has been prepared • A questionnare was sent to 35 centers in 2007, 10 replied

7. Cystic Fibrosis in Turkey University Patient number % Hacettepe 318 45.8 Marmara 195 28 Dokuz Eylül 49 7 Ege 39 5.6 Çukurova 37 5.3 Akdeniz 14 2 Erciyes 10 1.4 Uludağ 17 2.4 Celal Bayar 7 1 Ankara 5 0.7 Harran 3 0.4 Total 694 100

8. CF mutations

9. Detected CF mutations

10. Mutation frequency

11. CFTR mutations in Turkish CF patients Year Patient Detected Mutation Authors Center (n) mutation detection number(n) (%) 1995 67 …. 34.6 Yılmaz Ankara 1997 6 7 53.8 Angelicheva Bulgaria • 73 18 52.2 Onay İstanbul 2001 98 27 56.5 Onay İstanbul • 83 36 75 Kılınç İstanbul 2008 31 62.4 Lakeman Netherlands

12. Delta F508 mutation frequency in Turkish CF patients Year Patient DF508 Authors Center (n) (%) 1990 15 27 Hundreiser Germany • 25 20.3 Köprübaşı İzmir • 67 28.4 Yılmaz Ankara 1997 6 46 Angelicheva Bulgaria • 73 18.8 Onay İstanbul 2001 98 25 Onay İstanbul • 83 23.5 Kılınç İstanbul 2007 499 29.6 ........ Turkey

13. Frequency of other mutations in Turkish CF patients Onay, et al, 2001

14. Frequency of other mutations in Turkish CF patients Kılınç, et al, 2002

15. Hacettepe University Faculty of Medicine • Molecular Genetic Diagnosis Laboratory in Medical Biology Department • By using INNO-LiPA, CFTR17 and CFTR19 kits • Screening of 36 CFTR mutations • For patients with unknown mutations, indirect diagnostic analysis with polymorphic markers in CFTR genes (IVS6a-GATT, TUB18:intron 18 3601-65 A/C, TUB20 :intron 20 4006-200 A/C ) is performed for prenatal diagnosis

16. CF mutation frequency in Hacettepe University MutasyonlarSıklığı % delF50825.22 1677delTA5.22 N1303K4.25 2789+5GA3.05 G85E3.82 G542X2.62 2183AA-G2.07 R334W1.4 W1282X1.0 Diğerleri≤ 1 • Yılmaz E, et al. Study of 17 mutations in Turkish cystic fibrosis patients. Human Heredity 1995; 45;175-177. • Dayangaç D, et al. Mutations of the CFTR gene in Turkish patients with congenital bilateral absence of the vasdeferens. Hum Reprod 2004;19:1094-1100.

18. 51 males with CBAVD • 27 CF mutations • Mutation detection rate 72.5% • 2/3 patients have 2 CF mutations • Most common: IVS8-5T and D1152H mutations

20. CF in Turkey • Turkey is located at the crossroads of migration whereEurope meets Asia • The population is very ancient • Turkey has been a major route for migratorymovements, hosting a large number of different civilizations and accommodatingseveral populations • Turkey with its geographicallocation and historical background became a genetic bridge • This historical background possibly accounts for the high heterogeneity observed in the contemporary Turkish population

21. CF in Turkey • The disease is expected to befrequent but under diagnosed • Very little is known about the molecular basis of CF in the Turkish population • Most common mutations are not known • Low frequency of DF508 • Large numberof different mutations in the CFTR gene, rather thanother frequentmutations • The spectrum of mutations are similar to those of other Mediterraneanpopulations

22. CF in Turkey • Mediterranean region had the highest mutation heterogeneity • Anatolian population is one of the most geneticallyheterogeneous populations • Population of Turkeyhas the highest genetic heterogeneitywith respect to theCFTRlocus.

24. the geographicdistribution of 27,177 CF chromosomes • from 29 Europeancountries • 3 countries from the north ofAfrica • a total of 272 different CF mutations detectedin Europe • a questionnaire that was filled in by a • total of 63 laboratories/centres from 25 countries • M Özgüç, A Göçmen, H Erdem (Hacettepe School of Medicine, Ankara), Turkey

28. The DF508 mutation the highest relativefrequency in Denmark (87.2%) the lowest in Turkey (21.3%) • the frequency of DF508 In northern and central European countriesis 72.8%, in the Mediterraneanregion it is 56.8%. • Among the Mediterraneancountries, Algeria, Israel, Tunisia and Turkey havethe lowest relative frequencies of the DF508 mutation

29. Thethree most common CF mutations (DF508, G542X and N1303K) are present in most countries and regionsof Europe • The geographic distribution of the different CF mutations in Europe clearly shows that there is a high heterogeneity for CF mutations in the Mediterranean region

30. CF in Turkey • Genetic diagnosis of CF in Turkey is a difficult task • Genetic heterogeneity at the CFTR locus is very high • Detection of almost 60% of the mutations and haplotyping will possibly greatly improve genetic counseling in Turkey • We are a long way from population screening