Detection of Large Rearrangements in the Cystic Fibrosis Transmembrane Conductance Regulator Gene by Multiplex Ligation-Dependent Probe Amplification Assay When Sequencing Fails to Detect Two Disease-Causing Mutations

Aims: Most of the over 1600 mutations and sequence variants identified to date in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are point mutations or small deletions/insertions detectable by conventional sequencing. However, large rearrangements (deletions, duplications, or insertion/deletion mutations) have recently been reported to constitute 1–2% of CFTR mutations. The CFTR sequencing protocol at ARUP Laboratories interrogates the coding regions of all 27 exons and all intron/exon boundaries of the gene. This study was undertaken to determine whether testing for large gene rearrangements could improve the mutation detection rate. Results: Nine cases with abnormal quantitative pilocarpine iontophoresis sweat chloride (SC) values (>60 mEq/L) and 20 cases with borderline SC levels (40–60 mEq/L) with only one or no mutations detected by the ARUP 32 mutation panel, including the 23 mutations recommended by American College of Medical Genetics (ACMG) for carrier screening, followed by ...