A new largeCFTRrearrangement illustrates the importance of searching for complex alleles

Abstract

The p.Val754Met variant, described in 1996 in a CF patient, has been considered a CF mutation. However, biochemical aspects, results of functional studies and, finally, the identification of a complex deletion removing exons 3 to 10 and 14b to 16 in cis of p.Val754Met in a CF patient, argue against a strong deleterious effect. An inventory through the French CF network of patients carrying p.Val754Met led to the registration of seven patients (CF: n=4; idiopathic chronic pancreatitis: n=3) and six healthy individuals, all heterozygous for the variation. Extensive CFTR gene analysis was carried out, including the search for large rearrangements and other possible mutations. The complex deletion, whose breakpoints are described here, was found only in the four CF patients, in association with the same haplotype. This data, added to the fact that the p.[Phe508del]+[Val754Met] genotype was found in a healthy individual, bring further arguments against the association of p.Val754Met with CF. We thus suggest looking for a possible complex allele whenever p.Val754Met is detected and considering it neutral regarding genetic counseling when found in isolation.

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

“…CNMs in the CFTR gene have been extensively studied over the past 5 years by means of quantitative PCR techniques [Audrézet et al, 2004; Bombieri et al, 2005; Chevalier-Porst et al, 2005; Férec et al, 2006; Hantash et al, 2006; Loumi et al, 2008; Niel et al, 2004, 2006; Paracchini et al, 2008; Schneider et al, 2007; Schrijver et al, 2008; Taulan et al, 2009]. An array CGH method has recently been developed that has been used to screen CNMs in eight human disease genes including CFTR [Saillour et al, 2008].…”

Multiplex Ligation-Dependent Probe Amplification Identification of Whole Exon and Single Nucleotide Deletions in the CFTR Gene of Hispanic Individuals with Cystic Fibrosis

“…However, with the advent of techniques such as quantitative multiplex PCR of short fluorescent fragments, semiquantitative fluorescent PCR, semiquantitative fluorescent multiplex PCR, and MLPA, more genomic rearrangements in the CFTR gene have recently been identified, suggesting that exon deletions and duplications are of clinical importance in CF etiology (Table 1). 17,19,[31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48] Our work is the first exon rearrangement study to specifically target Hispanic patients with CF.…”

Detection of two Alu insertions in the CFTR gene

“…sickkids.on.ca/cftr/app; as of December 6, 2006), N97% are either single base-pair substitutions or microinsertions/deletions. Recently, however, an increasing number of large genomic rearrangements have been reported in the CFTR gene, a development potentiated by the introduction of quantitative PCR-based techniques [5][6][7][8][9][10][11][12][13][14][15]. Of the ∼ 30 such mutational events already documented in the literature, 21 have been fully characterized at the nucleotide level [10].…”