title: Complete ascertainment of intragenic copy number mutations (CNMs) in the CFTR gene and its implications for CNM formation at other autosomal loci.
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.
authors.affiliation: INSERM U613, and Université de Bretagne Occidentale, 46 rue Félix Le Dantec, Brest, France.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Quemener
authors.forename: Jian-Min
authors.initials: JM
authors.lastname: Chen
authors.forename: Nadia
authors.initials: N
authors.lastname: Chuzhanova
authors.forename: Caroline
authors.initials: C
authors.lastname: Bénech
authors.forename: Teresa
authors.initials: T
authors.lastname: Casals
authors.forename: Milan
authors.initials: M
authors.lastname: Macek
authors.forename: Thierry
authors.initials: T
authors.lastname: Bienvenu
authors.forename: Trudi
authors.initials: T
authors.lastname: McDevitt
authors.forename: Philip M
authors.initials: PM
authors.lastname: Farrell
authors.forename: Ourida
authors.initials: O
authors.lastname: Loumi
authors.forename: Taieb
authors.initials: T
authors.lastname: Messaoud
authors.forename: Harry
authors.initials: H
authors.lastname: Cuppens
authors.forename: Garry R
authors.initials: GR
authors.lastname: Cutting
authors.forename: Peter D
authors.initials: PD
authors.lastname: Stenson
authors.forename: Karine
authors.initials: K
authors.lastname: Giteau
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Audrézet
authors.forename: David N
authors.initials: DN
authors.lastname: Cooper
authors.forename: Claude
authors.initials: C
authors.lastname: Férec
mesh_terms: D001483:Base Sequence; D055028:Comparative Genomic Hybridization; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics*; D056426:Genetic Loci / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D009154:Mutation / Q000235:genetics*
chemical_list: D019005:Cystic Fibrosis Transmembrane Conductance Regulator