1. ¹Clinical Genetics Unit, Department of Pediatrics, University of Padova, Padova, Italy
2. ²Hematology-Oncology Laboratory, Department of Pediatrics, University of Padova, Padova, Italy

Correspondence: Professor M Clementi, Department of Pediatrics, Clinical Genetics Unit, University of Padova, via Giustiniani 3, Padova, Italy. E-mail: maurizio.clementi@unipd.it

³These authors contributed equally to this work.

Received 20 July 2009; Revised 13 October 2009; Accepted 14 October 2009; Published online 6 November 2009.

Abstract

The 621+3 A>G variant of the CFTR gene was initially detected in four Greek patients with a severe form of cystic fibrosis, and it is reported to impair CFTR mRNA splicing. We present three lines of evidence that argue against the pathogenicity of this variant. First, its allelic frequency in the Italian population was 0.4%. Even considering the lowest value in the confidence interval we would expect 10% of Italian CF patients to be heterozygotes for this variant, whereas it has been reported only in one patient (0.04% of Italian CF patients). Second, expression of the 621+3 A>G variant in HeLa cells using a hybrid minigene showed that 39.51.1% of transcripts were correctly spliced, indicating that its effects on mRNA splicing are similar to those of the CFTR intron 8 5T variant, associated with congenital bilateral absence of vas deferens (CBAVD), but not with CF. Third, we have identified an asymptomatic individual who harbored the 621+3 A>G variant in trans with the Q552X mutation. Because 621+3 A>G is often included in population-screening programs, this information is critical to provide adequate counseling to patients. Further work should be aimed at investigating whether this variant may have a role in CBAVD or atypical CF.