title: Variation in a repeat sequence determines whether a common variant of the cystic fibrosis transmembrane conductance regulator gene is pathogenic or benign.
abstract: An abbreviated tract of five thymidines (5T) in intron 8 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene is found in approximately 10% of individuals in the general population. When found in trans with a severe CFTR mutation, 5T can result in male infertility, nonclassic cystic fibrosis, or a normal phenotype. To test whether the number of TG repeats adjacent to 5T influences disease penetrance, we determined TG repeat number in 98 patients with male infertility due to congenital absence of the vas deferens, 9 patients with nonclassic CF, and 27 unaffected individuals (fertile men). Each of the individuals in this study had a severe CFTR mutation on one CFTR gene and 5T on the other. Of the unaffected individuals, 78% (21 of 27) had 5T adjacent to 11 TG repeats, compared with 9% (10 of 107) of affected individuals. Conversely, 91% (97 of 107) of affected individuals had 12 or 13 TG repeats, versus only 22% (6 of 27) of unaffected individuals (P<.00001). Those individuals with 5T adjacent to either 12 or 13 TG repeats were substantially more likely to exhibit an abnormal phenotype than those with 5T adjacent to 11 TG repeats (odds ratio 34.0, 95% CI 11.1-103.7, P<.00001). Thus, determination of TG repeat number will allow for more accurate prediction of benign versus pathogenic 5T alleles.
authors.affiliation: Training Program in Human Genetics, McKusick-Nathans Institute of Genetic Medicine, Baltimore, MD 21287, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Groman
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Hefferon
authors.forename: Teresa
authors.initials: T
authors.lastname: Casals
authors.forename: Lluís
authors.initials: L
authors.lastname: Bassas
authors.forename: Xavier
authors.initials: X
authors.lastname: Estivill
authors.forename: Marie
authors.initials: M
authors.lastname: Des Georges
authors.forename: Caroline
authors.initials: C
authors.lastname: Guittard
authors.forename: Monika
authors.initials: M
authors.lastname: Koudova
authors.forename: M Daniele
authors.initials: MD
authors.lastname: Fallin
authors.forename: Krisztina
authors.initials: K
authors.lastname: Nemeth
authors.forename: Gyorgy
authors.initials: G
authors.lastname: Fekete
authors.forename: Ludovit
authors.initials: L
authors.lastname: Kadasi
authors.forename: Ken
authors.initials: K
authors.lastname: Friedman
authors.forename: Martin
authors.initials: M
authors.lastname: Schwarz
authors.forename: Cristina
authors.initials: C
authors.lastname: Bombieri
authors.forename: Pier Franco
authors.initials: PF
authors.lastname: Pignatti
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Kanavakis
authors.forename: Maria
authors.initials: M
authors.lastname: Tzetis
authors.forename: Marianne
authors.initials: M
authors.lastname: Schwartz
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Novelli
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: D'Apice
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Sobczynska-Tomaszewska
authors.forename: Jerzy
authors.initials: J
authors.lastname: Bal
authors.forename: Manfred
authors.initials: M
authors.lastname: Stuhrmann
authors.forename: Milan
authors.initials: M
authors.lastname: Macek
authors.forename: Mireille
authors.initials: M
authors.lastname: Claustres
authors.forename: Garry R
authors.initials: GR
authors.lastname: Cutting
mesh_terms: D001483:Base Sequence; D003550:Cystic Fibrosis / Q000235:genetics; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D018900:Dinucleotide Repeats / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D012016:Reference Values
chemical_list: C505032:CFTR protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator