title: Is CFTR 621+3 A>G a cystic fibrosis causing mutation?
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 39.5+/-1.1% 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.
authors.affiliation: Clinical Genetics Unit, Department of Pediatrics, Universita di Padova, via Giustiniani 3, Padua, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Forzan
authors.forename: Leonardo
authors.initials: L
authors.lastname: Salviati
authors.forename: Vanessa
authors.initials: V
authors.lastname: Pertegato
authors.forename: Alberto
authors.initials: A
authors.lastname: Casarin
authors.forename: Alice
authors.initials: A
authors.lastname: Bruson
authors.forename: Eva
authors.initials: E
authors.lastname: Trevisson
authors.forename: Elena
authors.initials: E
authors.lastname: Di Gianantonio
authors.forename: Maurizio
authors.initials: M
authors.lastname: Clementi
mesh_terms: D002648:Child; D003550:Cystic Fibrosis / Q000235:genetics*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005787:Gene Frequency; D006367:HeLa Cells; D006579:Heterozygote; D006801:Humans; D007248:Infertility, Male / Q000209:etiology; D007558:Italy; D008297:Male; D009154:Mutation; D012326:RNA Splicing; D014649:Vas Deferens / Q000002:abnormalities
chemical_list: C505032:CFTR protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator