CFTR 5T variant has a low penetrance in females that is partially attributable to its haplotype.
OBJECTIVE
The study's purpose was to understand the molecular basis for different clinical phenotypes of the 5T variant, a tract of 5 thymidines in intron 8 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which disrupts processing of CFTR mRNA and reduces synthesis from the corresponding CFTR alleles.


METHODS
We analyzed the polymorphic TG dinucleotide repeat adjacent to the 5T variant in intron 8 and the codon 470 in exon 10. Patients selected for this study were positive for both the 5T variant and the major cystic fibrosis mutation, Delta F508. Almost all Delta F508 mutation alleles occur in a 10TG-9T-470M haplotype. Therefore, it is possible to determine the haplotype of the 5T variant in trans.


RESULTS
Of the 74 samples analyzed, 41 (55%) were 11TG-5T-470M, 31 (42%) were 12TG-5T-470V, and 2 (3%) were 13TG-5T-470M. Of the 49 cases for which we had clinical information, 17.6% of females (6/34) and 66.7% of males (10/15) showed symptoms resembling atypical cystic fibrosis. The haplotype with the highest penetrance in females (42% or 5/12) and more than 80% (5/6) in males is 12TG-5T-470V. We also evaluated 12 males affected with congenital bilateral absence of vas deferens and positive for the 5T variant; 10 of 12 had the 12TG-5T-470V haplotype.


CONCLUSIONS
Overall, the 5T variant has a milder clinical consequence than previously estimated in females. The clinical presentations of the 5T variant are associated with the 5T-12TG-470M haplotype.
Sun
Weimin
W
Department of Molecular Genetics, Quest Diagnostics Nichols Institute, San Juan Capistrano, California 92690, USA.
Anderson
Ben
B
Redman
Joy
J
Milunsky
Aubrey
A
Buller
Arlene
A
McGinniss
Matthew J
MJ
Quan
Franklin
F
Anguiano
Arturo
A
Huang
Stephen
S
Hantash
Feras
F
Strom
Charles
C
D000483:Alleles; D001483:Base Sequence; D003550:Cystic Fibrosis / Q000235:genetics*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005817:Genetic Counseling; D006239:Haplotypes / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008297:Male; D009154:Mutation; D009845:Oligospermia / Q000235:genetics; D019683:Penetrance; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics; D017384:Sequence Deletion; D013936:Thymidine / Q000235:genetics; D014649:Vas Deferens / Q000002:abnormalities
D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D013936:Thymidine