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Rapid detection of CFTR gene rearrangements impacts on genetic counselling in cystic fibrosis
  1. F Niel,
  2. J Martin,
  3. F Dastot-Le Moal,
  4. B Costes,
  5. B Boissier,
  6. V Delattre,
  7. M Goossens,
  8. E Girodon
  1. Service de Biochimie et Génétique, AP-HP et INSERM U468, Hôpital Henri-Mondor, 94010 Créteil, France
  1. Correspondence to:
 Emmanuelle Girodon
 Service de Biochimie et Génétique, AP-HP et INSERM U468, Hôpital Henri-Mondor, 94010 Créteil, France; Emmanuelle.Girodonim3.inserm.fr

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Cystic fibrosis (CF) (MIM 219700) is one of the most common autosomal recessive diseases in Caucasians.1 It affects about 1 in 2500 births and approximately 1 in 25 individuals are heterozygotes, with marked regional variations2 (www.genet.sickkids.on.ca/cftr). It is caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR or ABCC7) gene (MIM 602421), which is also involved in a broad spectrum of phenotypes, including male infertility by congenital bilateral absence of the vas deferens (CBAVD),3–5 disseminated bronchiectasis (DB),6,7 and chronic pancreatitis.8,9 So far, over 1000 CFTR gene mutations have been described throughout the gene, along with geographic and ethnic variations in their distribution and frequency (www.genet.sickkids.on.ca/cftr).2,10 Of these variations, 99% consist of point mutations or micro-deletions/insertions (www.genet.sickkids.on.ca/cftr) but account for 33–98% of CF alleles, depending on the population.10 A number of cases remain unsolved after extensive and laborious screening of the 27 exons, thus making genetic counselling difficult for the patients and their families, particularly when the CF diagnosis is not certain. Unidentified CF mutations may lie in introns or in regulatory regions which are not routinely investigated, or correspond to gene rearrangements such as large deletions at the heterozygous state which escape detection using current PCR based techniques. Deletions have been suspected in a very few situations: upon failure of PCR amplification to target particular exons when the deletions were present in CF patients in the homozygous state, or in cases of abnormal segregation of a mutation or polymorphisms in a family. Two such deletions, CFTRdele2–311 and CFTRdele17a–18,12 which are now routinely tested for by conventional PCR using specific primers, were found in about 5% and 13% of CF chromosomes in Slav and Arab populations, respectively.

Screening for unknown CFTR deletions still …

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    • [View PDF] - Figure 1 Electropherograms from semi-quantitative fluorescent multiplex PCR experiments. The x axis displays the computed length of the PCR products in base pairs as determined by using an internal lane standard, which is indicated in black. The y axis shows fluorescent intensities in arbitrary units. Gene fragments are indicated at the top of the corresponding peaks. The electropherograms of the controls are in red and those of the patients are in blue. The profiles were superimposed and normalised using the exon 4 DSCR1 amplicon. The abnormal profiles have been highlighted by arrows and extended (windows). (A) CFTRdele17a�17b visualised from MP 3 in patient no. 7 (twofold decrease in peak intensities for exons 17a and 17b). (B) CFTRdele1�24, visualised from MP 2 in patient no. 10 (twofold decrease in peak intensity for all CFTR exons). For CFTR exon 9, the presence of a double peak in the control is attributable to the (TG)mTn polymorphism. (C) CFTRdup4�8, visualised from MP 1 in patient no. 11�s mother (1.5-fold increase in peak intensity for exons 4�6a). She carries in trans the �912dupT polymorphism in the promoter region (double peak).

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