1. ¹INSERM, U613 (Génétique Moléculaire et Génétique Epidémiologique), Brest, France
2. ²Université de Bretagne Occidentale, Faculté de Médecine de Brest et des Sciences de la Santé, Brest, France
3. ³Etablissement Français du Sang – Bretagne, Brest, France
4. ⁴CHRU Brest, Hôpital Morvan, Laboratoire de Génétique Moléculaire et d'Histocompatibilité, Brest, France
5. ⁵Medical and Molecular Genetics Center-IRO, Hospital Duran i Reynals, Barcelona, Spain
6. ⁶Biostatistics and Bioinformatics Unit, Cardiff University, Cardiff, UK
7. ⁷Institute of Biology and Medical Genetics-Cystic Fibrosis Center, Charles University, Prague, Czech Republic
8. ⁸Laboratoire de Biochimie et Génétique Moléculaire, Hôpital Cochin, Paris, France
9. ⁹National Centre for Medical Genetics and Department of Paediatrics, University College Dublin, Our Lady's Hospital for Sick Children, Crumlin, Dublin, Ireland
10. ¹⁰Cystic Fibrosis Centre, Azienda Ospedaliera di Verona, Verona, Italy
11. ¹¹Department of Pediatrics, University of Wisconsin Medical School, Madison, WI, USA
12. ¹²Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
13. ¹³Genetic Health Services Victoria, Royal Children's Hospital, Parkville, Australia
14. ¹⁴Faculté des Sciences Biologiques, Bab-Ezzouar Institut de Biologie, Université des Sciences et de la Technologie, Alger, Algeria
15. ¹⁵Laboratoire de Biochimie, Clinique-Hopital d'Enfants, Tunis, Tunisia
16. ¹⁶Center for Human Genetics, Catholic University of Leuven, Leuven, Belgium
17. ¹⁷Unita' Operativa Citogenetica e Genetica, Azienda Ospedaliera Careggi, Florence, Italy
18. ¹⁸Murdoch Children's Research Institute, Parkville, Australia
19. ¹⁹Laboratorio de Genética-B2-IBGM, Instituto de Biologia y Genética Molecular, Valladolid, Spain
20. ²⁰Section of Biology and Genetics, University of Verona, Verona, Italy
21. ²¹Institute of Medical Genetics, Cardiff University, Cardiff, UK

Correspondence: Professor C Férec, INSERM, U613, Université de Bretagne Occidentale, Etablissement Français du Sang – Bretagne, 46 rue Félix Le Dantec, Brest, F-29220 France. Tel: +33 2 98445064; Fax: +33 2 98430555; E-mail: claude.ferec@univ-brest.fr

Received 24 October 2005; Revised 6 January 2006; Accepted 10 January 2006; Published online 22 February 2006.

Abstract

Gross genomic rearrangements involving deletions in the CFTR gene have recently been found to account for 20% of unidentified cystic fibrosis (CF) chromosomes in both French and Italian patients. Using QMPSF and walking quantitative DHPLC, six novel mutations (three simple deletions, two complex deletions with short insertions of 3–6 bp, and a complex deletion with a 182 bp inverted downstream sequence) were characterized by screening 274 unidentified CF chromosomes from 10 different countries. These lesions increase the total number of fully characterized large CFTR genomic rearrangements involving deletions to 21. Systematic analysis of the 42 associated breakpoints indicated that all 21 events were caused by nonhomologous recombination. Whole gene complexity analysis revealed a significant correlation between regions of low sequence complexity and the locations of the deletion breakpoints. Known recombination-promoting motifs were noted in the vicinity of the breakpoints. A total of 11 simple deletions were potentially explicable in terms of the classical model of replication slippage. However, the complex deletions appear to have arisen via multiple mechanisms; three of the five complex deletions with short insertions and both examples of large inverted insertions (299 and 182 bp, respectively) can be explained by either a model of serial replication slippage in cis (SRScis) or SRS in trans (SRStrans). Finally, the nature and distribution of large genomic rearrangements in the CFTR gene were compared and contrasted with those of two other genes, DMD and MSH2, with a view to gaining a broader understanding of DNA sequence context in mediating the diverse underlying mutational mechanisms.