title: CFTR 5T variant has a low penetrance in females that is partially attributable to its haplotype.
abstract: 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.
authors.affiliation: Department of Molecular Genetics, Quest Diagnostics Nichols Institute, San Juan Capistrano, California 92690, USA.
authors.forename: Weimin
authors.initials: W
authors.lastname: Sun
authors.forename: Ben
authors.initials: B
authors.lastname: Anderson
authors.forename: Joy
authors.initials: J
authors.lastname: Redman
authors.forename: Aubrey
authors.initials: A
authors.lastname: Milunsky
authors.forename: Arlene
authors.initials: A
authors.lastname: Buller
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: McGinniss
authors.forename: Franklin
authors.initials: F
authors.lastname: Quan
authors.forename: Arturo
authors.initials: A
authors.lastname: Anguiano
authors.forename: Stephen
authors.initials: S
authors.lastname: Huang
authors.forename: Feras
authors.initials: F
authors.lastname: Hantash
authors.forename: Charles
authors.initials: C
authors.lastname: Strom
mesh_terms: 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
chemical_list: D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D013936:Thymidine