Variable Penetrance And Expressivity of The Splice Altering 5T Sequence in The Cystic Fibrosis Gene

This manuscript reviews the frequencies, symptoms, testing, and reporting of genotypes with the 5T polythymidine tract which reduces splicing efficiency in the cystic fibrosis transmembrane conductance regulator (CFTR) gene in congenital bilateral absence of the vas deferens (CBAVD) patients and in patients and fetuses with cystic fibrosis-like symptoms. The 5T sequence has not been included in the American College of Medical Genetics (ACMG) CFTR mutation panel recommended for screening pregnant women for an increased fetal risk of cystic fibrosis (CF; MIM 219700) because finding this allele would raise concern for possible CFTR gene-related symptoms in many fetuses, even though only a fraction inheriting 5T and another major CFTR mutation would develop CF-like symptoms. In contrast, 40–80% of the symptomatic patients with CBAVD (MIM 277180) are compound heterozygotes for the 5T sequence. This submission provides template report summaries for CBAVD patient results for the 5T allele when tested along with the 23 most common ACMG mutation panel. If CBAVD patients were also tested with the remaining 16 most common reported mutations in CBAVD, the derived proportion of patients with at least one CFTR mutant allele is predicted to increase from 63% to 97%. Testing for the 5T sequence in symptomatic patients and reflex 5T testing in fetuses found to carry a major CF allele are discussed because finding the 5T sequence in these patients lowers the risk of typical severe symptoms. Additional reflex testing for the number of TG repeats adjacent to a 5T allele further modifies the predicted long-term severity of disease symptoms in patients and fetuses that are compound heterozygotes for a major CF mutation and the 5T sequence. Even though patient advice can be modified currently based upon the adjacent TG-repeat number, the final most accurate risk frequencies with different 5T + TG-repeat alleles are likely to become available only after a statistically robust study of a substantially larger patient population is completed with multiple well-defined clinical and mutation categories.