High Variability Found in People With F508del/5T;TG12 Genotype
There is wide clinical variety in the presentation of individuals who carry one F508del mutation and one 5T;TG12 mutation in the CFTR gene, an Italian study highlights.
Its researchers stressed the need to monitor individuals with this genotype, since there are not currently accurate ways to predict who is at highest risk of developing severe disease.
The study, “Clinical outcomes of a large cohort of individuals with the F508del/5T;TG12 CFTR genotype,” was published in the Journal of Cystic Fibrosis.
Cystic fibrosis (CF) is caused by mutations in the gene CFTR. Nearly 2,000 mutations in this gene have been documented, though not all of them cause the development of CF. Defining the particular clinical characteristics commonly associated with specific mutations is an active area of research.
A CFTR mutation called 5T;TG12 is characterized by a small sequence of the genetic code being repeated more than is usual, which can interfere with the production of CFTR protein when the gene is “read.”
Everyone inherits two copies of this gene, one from each biological parent. Previous research assessing the clinical presentation of people who carry one copy of CFTR with the 5T;TG12 mutation has found a wide range of results: some people carrying this mutation develop CF, while others develop only milder CFTR-related disorders, or no disease at all.
This variation is likely influenced substantially by the other copy of CFTR that patients carry. Here, researchers in Italy sought to control for this variation by assessing clinical outcomes for patients who carried the same two CFTR mutations: one copy of the 5T;TG12 mutation and one copy of F508del, the most common CF-causing mutation.
The analysis included data for 129 people followed at one of 10 centers in Italy. Among the patients, 54 were female, and ages ranged from less than a year to 58 years, with a median age of 15 years.
Initially, 23.3% of the patients had been diagnosed with CF, while 31.7% were diagnosed with CFTR-related disorders. The remaining patients were categorized under an inconclusive diagnosis termed CRMS/CFSPID (cystic fibrosis transmembrane conductance regulator-related metabolic syndrome/cystic fibrosis screen positive, inconclusive diagnosis).
After a mean follow-up time of 6.7 years, nine of the patients initially diagnosed with CFTR-related disorders progressed to CF, as did six of those with CRMS/CFSPID. These diagnostic changes were made based on sweat chloride tests and/or the appearance of clear CF-like symptoms. By the end of follow-up, 34.9% of patients had been diagnosed with CF.
“We showed that a significant number of subjects, initially diagnosed with CRMS/CFSPID or CFTR-[related disorders], may progress to CF over time,” the researchers wrote. “This result strongly suggested that long-term follow-up is necessary because currently there are no markers for the identification of patients with higher risks of more severe outcomes.”
Regardless of diagnosis, the vast majority of individuals in this analysis had lung function within normal ranges, defined as forced expiratory volume higher than 90% predicted. Moderate lung function impairment was present in 4.9% of those diagnosed with CF and 10.5% of those diagnosed with CFTR-related disorders. Only one patient (diagnosed with CF) had severely impacted lung function.
Congenital bilateral absence of the vas deferens (CBAVD), when the tube that transports sperm from the testes during ejaculation is absent, was present in 95.2% of males diagnosed with CF and in all of the males with CFTR-related disorders. None of the patients with CRMS/CFSPID had CBAVD.
Over the course of follow-up, 13.3% of CF patients, and 5.7% of those with CFTR-related disorders, required antibiotic treatment for a lung exacerbation. None of those with CRMS/CFSPID required such treatment.
All in all, despite the fact that all of these individuals carried the same two mutations in the CFTR gene, “the clinical expression of these subjects varied,” the researchers concluded.
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