A new large CFTR rearrangement illustrates the importance of searching for complex alleles

Hum Mutat. 2006 Jul;27(7):716-7. doi: 10.1002/humu.9431.


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.

MeSH terms

  • Adolescent
  • Adult
  • Alleles*
  • Base Sequence
  • Child
  • Chromosome Aberrations*
  • Cystic Fibrosis / diagnosis
  • Cystic Fibrosis / genetics*
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics*
  • DNA Mutational Analysis
  • Female
  • Genetic Testing
  • Haplotypes
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Middle Aged
  • Mutation, Missense
  • Polymorphism, Genetic
  • Sequence Deletion


  • CFTR protein, human
  • Cystic Fibrosis Transmembrane Conductance Regulator