Short Report Cystic fibrosis in Greece: molecular diagnosis, haplotypes, prenatal diagnosis and carrier identification amongst high-risk individuals E Kanavakis a , A Efthymiadou a , S Strofalis a , S Doudounakis b , J Traeger-Synodinos a and M Tzetis a a Medical Genetics, Athens University; b Cystic Fibrosis Unit, ‘Aghia Sophia’ Children’s Hospital, Athens, Greece Key words: cascade screening – CFTR mutations – echogenic bowel – haplotypes – prenatal diagnosis Corresponding author: Maria Tzetis, PhD, Research Associate Genetics, Department of Medical Genetics, Athens University, ‘Aghia Sophia’ Children’s Hospital, Thivon & Livadias, Athens, 11527, Greece. Tel.: þ3010 7467461; fax: þ3010 7795553; e-mail: mtzeti@cc.uoa.gr Received 16 October 2002, revised and accepted for publication 20 December 2002 Kanavakis E, Efthymiadou A, Strofalis S, Doudounakis S, Traeger-Synodinos J, Tzetis M. Cystic fibrosis in Greece: molecular diagnosis, haplotypes, prenatal diagnosis and carrier identification amongst high-risk individuals. Clin Genet 2003: 63: 400–409. # Blackwell Munksgaard, 2003 Cystic fibrosis (CF) mutation analysis on 437 CF patients, characterized 80 different mutations (20 so far specific to our population) accounting for 91% of CF genes and generating 103 different genotypes. Eight mutations were common [F508del (53.4%), 621þ1G>T (5.7%), G542X (3.9%), N1303K (2.6%), 2789þ5G>A (1.7%), 2183AA>G (1.4%), E822X (1.4%), R1158X (1%)], 12 showed frequencies between 0.5% and 1%, while the remaining (60) were very rare (1 to 3 alleles). Denaturing gradient gel electrophoresis (DGGE) screening of 12 exons (3,4,7,10,11,13,14b,16,17b20and21)detected85.5% of CF alleles. Haplotypesforeightdiallelicandthreemicrosatellitemarkershavebeen characterized for the common, a few rare and novel Greek mutations. Results of 165 prenatal diagnoses (including 49 due to bowel hyperechogenicity),testingatotalof41differentparentalgenotypes,are reported. One hundred and sixteen prenatal tests resulted in 22 affected, 59heterozygous,34normalfetusesandoneincompletediagnosis.Ofthe 49 echogenic bowel fetuses, 3 were heterozygotes. Carrier screening was initiated,withemphasisonindividualsandcouplesinhigh-riskgroups– withafamilyhistoryofCF,onepartnerwithCF,andcoupleswithmale infertility seeking in vitro fertilization (IVF). Mutation analysis on 672 individuals (120 couples, 91 unaffected CF siblings, 283 CF family relatives and 58 general population subjects), identified a total of 176 heterozygotes and 7 couples where both partners were CF heterozygotes. Prenatal diagnosis was performed in 4 cases and 3 were counseled on the availability of a prenatal test. Cystic fibrosis (CF; MIM no. 219700, CFTR; MIM no. 602421) is a severe autosomal recessive genetic disease, affecting 1 in 2500 Caucasians with 4% being asymptomatic carriers ofmutationsinthegene (1–4).Thereissubstantial variability in the clinical expression of the disease, with patients symptomatic at birth, while others not presenting symptoms for months or evenyears.CFTRisexpressedinseveralcelltypes of the airway, has multiple functions in epithelial cells and mutations in the CFTR gene have been found in several lung disorders (5). Since the initial characterization of the pre- dominant mutation in the Caucasian population, F508del(2),morethan1000mutationshavebeen reported to the Cystic Fibrosis Genetic Analysis Consortium (CFGAC) (6), most of which are presumed to be pathogenic. Complex alleles, in which more than one mutation is present in cis, have been observed (7). F508del shows a higher frequencyinnorthernEuropeanincomparisonto southern European populations (1), where the percentage of non-F508del chromosomes asso- ciated with CF is high. The frequencies and Clin Genet 2003: 63: 400–409 Copyright # Blackwell Munksgaard 2003 Printed in Denmark. All rights reserved CLINICAL GENETICS ISSN 0009-9163 400