Complete ascertainment of intragenic copy number mutations (CNMs) in the CFTR gene and its implications for CNM formation at other autosomal loci

Authors

  • Sylvia Quemener,

    1. Institut National de la Santé et de la Recherche Médicale (INSERM), U613, Brest, France
    2. Faculté de Médecine et des Sciences de la Santé, Université de Bretagne Occidentale (UBO), Brest, France
    3. Etablissement Français du Sang (EFS)—Bretagne, Brest, France
    4. Laboratoire de Génétique Moléculaire et d'Histocompatibilité, Centre Hospitalier Universitaire (CHU), Hôpital Morvan, Brest, France
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  • Jian-Min Chen,

    Corresponding author
    1. Institut National de la Santé et de la Recherche Médicale (INSERM), U613, Brest, France
    2. Faculté de Médecine et des Sciences de la Santé, Université de Bretagne Occidentale (UBO), Brest, France
    3. Etablissement Français du Sang (EFS)—Bretagne, Brest, France
    • EFS—Bretagne, 46 rue Félix Le Dantec, 29218 Brest, France
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  • Nadia Chuzhanova,

    1. School of Computing, Engineering and Physical Sciences, University of Central Lancashire, Preston PR1 2HE, United Kingdom
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  • Caroline Bénech,

    1. Institut National de la Santé et de la Recherche Médicale (INSERM), U613, Brest, France
    2. Etablissement Français du Sang (EFS)—Bretagne, Brest, France
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  • Teresa Casals,

    1. Medical and Molecular Genetics Center-IDIBELL, Hospital Duran i Reynals, Barcelona, Spain
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  • Milan Macek Jr.,

    1. Institute of Biology and Medical Genetics-Cystic Fibrosis Center, Charles University, Prague, Czech Republic
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  • Thierry Bienvenu,

    1. Laboratoire de Biochimie et Génétique Moléculaire, Hôpital Cochin, Paris, France
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  • Trudi McDevitt,

    1. National Centre for Medical Genetics and Department of Paediatrics, University College Dublin, Our Lady's Hospital for Sick Children, Dublin, Ireland
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  • Philip M. Farrell,

    1. Department of Pediatrics, University of Wisconsin Medical School, Madison, WI
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  • Ourida Loumi,

    1. Faculté des Sciences Biologiques, Bab-Ezzouar Institut de Biologie, Université des Sciences et de la Technologie, Alger, Algeria
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  • Taieb Messaoud,

    1. Laboratoire de Biochimie, Clinique-Hopital d'Enfants, Tunis, Tunisia
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  • Harry Cuppens,

    1. Center for Human Genetics, Catholic University of Leuven, Leuven, Belgium
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  • Garry R. Cutting,

    1. Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
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  • Peter D. Stenson,

    1. Institute of Medical Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, United Kingdom
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  • Karine Giteau,

    1. Laboratoire de Génétique Moléculaire et d'Histocompatibilité, Centre Hospitalier Universitaire (CHU), Hôpital Morvan, Brest, France
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  • Marie-Pierre Audrézet,

    1. Institut National de la Santé et de la Recherche Médicale (INSERM), U613, Brest, France
    2. Laboratoire de Génétique Moléculaire et d'Histocompatibilité, Centre Hospitalier Universitaire (CHU), Hôpital Morvan, Brest, France
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  • David N. Cooper,

    1. Institute of Medical Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, United Kingdom
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  • Claude Férec

    Corresponding author
    1. Institut National de la Santé et de la Recherche Médicale (INSERM), U613, Brest, France
    2. Faculté de Médecine et des Sciences de la Santé, Université de Bretagne Occidentale (UBO), Brest, France
    3. Etablissement Français du Sang (EFS)—Bretagne, Brest, France
    4. Laboratoire de Génétique Moléculaire et d'Histocompatibilité, Centre Hospitalier Universitaire (CHU), Hôpital Morvan, Brest, France
    • INSERM, U613 and Université de Bretagne Occidentale (UBO), 46 rue Félix Le Dantec, 29218 Brest, France
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  • Communicated by Mireille Claustres

Abstract

Over the last 20 years since the discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, more than 1,600 different putatively pathological CFTR mutations have been identified. Until now, however, copy number mutations (CNMs) involving the CFTR gene have not been methodically analyzed, resulting almost certainly in the underascertainment of CFTR gene duplications compared with deletions. Here, high-resolution array comparative genomic hybridization (averaging one interrogating probe every 95 bp) was used to analyze the entire length of the CFTR gene (189 kb) in 233 cystic fibrosis chromosomes lacking conventional mutations. We succeeded in identifying five duplication CNMs that would otherwise have been refractory to analysis. Based upon findings from this and other studies, we propose that deletion and duplication CNMs in the human autosomal genome are likely to be generated in the proportion of approximately 2–3:1. We further postulate that intragenic gene duplication CNMs in other disease loci may have been routinely underascertained. Finally, our analysis of ±20 bp flanking each of the 40 CFTR breakpoints characterized at the DNA sequence level provide support for the emerging concept that non-B DNA conformations in combination with specific sequence motifs predispose to both recurring and nonrecurring genomic rearrangements. Hum Mutat 31:1–8, 2010. © 2010 Wiley-Liss, Inc.

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