Variation in a repeat sequence determines whether a common variant of the cystic fibrosis transmembrane conductance regulator gene is pathogenic or benign.
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.
Groman
Joshua D
JD
Training Program in Human Genetics, McKusick-Nathans Institute of Genetic Medicine, Baltimore, MD 21287, USA.
Hefferon
Timothy W
TW
Casals
Teresa
T
Bassas
Lluís
L
Estivill
Xavier
X
Des Georges
Marie
M
Guittard
Caroline
C
Koudova
Monika
M
Fallin
M Daniele
MD
Nemeth
Krisztina
K
Fekete
Gyorgy
G
Kadasi
Ludovit
L
Friedman
Ken
K
Schwarz
Martin
M
Bombieri
Cristina
C
Pignatti
Pier Franco
PF
Kanavakis
Emmanuel
E
Tzetis
Maria
M
Schwartz
Marianne
M
Novelli
Giuseppe
G
D'Apice
Maria Rosaria
MR
Sobczynska-Tomaszewska
Agnieszka
A
Bal
Jerzy
J
Stuhrmann
Manfred
M
Macek
Milan
M
Claustres
Mireille
M
Cutting
Garry R
GR
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
C505032:CFTR protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator