Cystic Fibrosis Mutations in Turkey

Prof. Dr. Deniz Doğru ErsözHacettepe University Faculty of

Medicine Pediatric Pulmonary Medicine Unit

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)

CF Gene

CF gene codes for a protein of 1480 amino acids , called

“CF transmembrane regulator (CFTR) protein”

CFTR

CFTR mutations

Severe Mild

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

Cystic Fibrosis in TurkeyUniversity Patient number %

Hacettepe 318 45.8Marmara 195 28Dokuz Eylül 49 7Ege 39 5.6Çukurova 37 5.3Akdeniz 14 2Erciyes 10 1.4Uludağ 17 2.4Celal Bayar 7 1Ankara 5 0.7Harran 3 0.4

Total 694 100

CF mutations

26%

74%

UnknownKnown

Detected CF mutations

22%

46%

32%

F508del/F508del

F508del/other

Other/other

Mutation Frequency

%

Delta F508 173 29.6

1677delTA 24 4.1

N1303K 22 3.8

G85E 12 2.1

W1282X 7 1.2

G542X 9 1.5

I148T 4 0.7

2789+56A 4 0.7

2183AAG 3 0.5

R1066L 2 0.3

A46D 2 0.3

Ex2del 2 0.3

R347P 2 0.3

L812X 1 0.2

Mutation Frequency

%

E831X 1 0.2

S1235R 1 0.2

G551D 1 0.2

621+1G>T 1 0.2

E92K 1 0.2

3199del6 1 0.2

833AA>G 1 0.2

D1152 1 0.2

R343W 1 0.2

183AAG 1 0.2

1853C 1 0.2

435insA 1 0.2

W1282X 1 0.2

Total 584 100

Mutation frequency

CFTR mutations in Turkish CF patients

Year Patient Detected Mutation Authors Center (n) mutation detection number(n) (%)

1995 67 …. 34.6 YılmazAnkara

1997 6 7 53.8 Angelicheva Bulgaria1998 73 18 52.2 Onay İstanbul2001 98 27 56.5 Onay İstanbul2002 83 36 75 Kılınç İstanbul2008 31 62.4 Lakeman Netherlands

Delta F508 mutation frequency in Turkish CF patients

Year Patient DF508 AuthorsCenter

(n) (%)1990 15 27 Hundreiser Germany1993 25 20.3 Köprübaşı İzmir1995 67 28.4 Yılmaz

Ankara1997 6 46 Angelicheva Bulgaria1998 73 18.8 Onay İstanbul2001 98 25 Onay İstanbul2002 83 23.5 Kılınç İstanbul2007 499 29.6 ........ Turkey

Frequency of other mutations in Turkish CF patients

Onay, et al, 2001

Frequency of other mutations in Turkish CF patients

Kılınç, et al, 2002

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

CF mutation frequency in Hacettepe University

Mutasyonlar Sıklığı %

delF508 25.221677delTA 5.22N1303K 4.252789+5GA 3.05G85E 3.82G542X 2.622183AA-G 2.07 R334W 1.4W1282X 1.0Diğerleri ≤ 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.

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

CF in Turkey Turkey is located at the crossroads of migration

where Europe meets Asia

The population is very ancient

Turkey has been a major route for migratory movements, hosting a large number of different civilizations and accommodating several populations

Turkey with its geographical location and historical background became a genetic bridge

This historical background possibly accounts for the highheterogeneity observed in the contemporary Turkish population

CF in Turkey The disease is expected to be frequent but under

diagnosed

Very little is known about the molecular basis of CFin the Turkish population

Most common mutations are not known

Low frequency of DF508

Large number of different mutations in theCFTR gene, rather than other frequent mutations

The spectrum of mutations are similar to those of other Mediterranean populations

CF in Turkey Mediterranean region had the highest

mutation heterogeneity

Anatolian population is one of the most genetically heterogeneous populations

Population of Turkey has the highest genetic heterogeneity with respect to the CFTRlocus.

the geographic distribution of 27,177 CF chromosomes from 29 European countries 3 countries from the north of Africa a total of 272 different CF mutations detected in

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

The DF508 mutation the highest relative frequency in Denmark

(87.2%)the lowest in Turkey (21.3%)

the frequency of DF508 In northern and central European countries is

72.8%, in the Mediterranean region it is 56.8%.

• Among the Mediterranean countries, Algeria, Israel, Tunisia and Turkey have the lowest relative frequenciesof the DF508 mutation

The three most common CF mutations (DF508, G542Xand N1303K) are present in most countries andregions of Europe

The geographic distribution of the different CFmutations in Europe clearly shows that there is a highheterogeneity for CF mutations in the Mediterraneanregion

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