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.

The CFTR polymorphisms poly-T, TG-repeats and M470V in Chinese males with congenital bilateral absence of the vas deferens

“…13 TG11-5T was by far the most common in United States, Czech Republic, Poland, Italy and Germany populations, followed by TG12-5T and TG13-5T. 13 However, our study showed that TG11-5T was not found in the normal Chinese population ( Table 4). Ethnic differences in the incidence of CFTR (TG)m(T)n around the world are quite striking.…”

“…13 In 72 cases with 97 alleles of IVS8-5T present in 109 Chinese CBAVD patients, 70 cases (97.22%) and 94 alleles (96.91%) had 12 or 13 TG repeats adjacent to 5T. TG12-5T was the most common disease-associated combination, and was found in 33.94% of the Chinese CBAVD patients versus 13.46% of controls ( Table 4).…”

“…Prior studies have demonstrated that a 5T variant, along with the preceding higher repetitive dinucleotide TG sequences such as (TG)13 or (TG)12, produces more mRNA transcripts with inframe deletion of exon 9. 11,15, 28 Groman et al 13 suggested that TG repeat number is a reliable predictor of penetrance for pathogenic 5T alleles. Those individuals carrying TG12-5T or TG13-5T were substantially more likely to exhibit an abnormal phenotype than those carrying TG11-5T.…”

“…11,12 Prior studies have demonstrated that the disease penetrance of 5T depends on the copy number of its adjacent TG repeats. 13,14 The number of TG repeats immediately adjacent to 5T is associated with a variable efficiency of exon 9 splicing. 15,16 The different alleles at (TG)m(T)n polymorphic loci at the 39 end of human CFTR intron 8 determine the exon 9 splicing efficiency.…”

TGFB-induced factor (TGIF): a candidate gene for psychosis on chromosome 18p

“…Haplotypic backgrounds, including variations in introns, have been known to influence the severity of an associated phenotype caused by an exonic variant. 39 TGIF is a member of the TALE superclass of homeobox proteins. The genes encoding these proteins are highly conserved in different species.…”