Extensive CFTR Gene Analysis Revealed a Higher Occurrence of Cystic Fibrosis Transmembrane Regulator-Related Disorders (CFTR-RD) among CF Carriers

Abstract

Background: A wide range of cystic fibrosis (CF)-related conditions are reported in CF carriers, but no study has explored the possibility that such subjects may be affected by cystic fibrosis transmembrane regulator-related disorders (CFTR-RD). No data are available so far on the occurrence of CFTR-RD among CF carriers. Methods: We studied 706 CF carriers—first- and second-degree relatives of CF patients that carried the parental mutation; such subjects were divided in two groups: a first group (353 subjects, group A) performed at first only the analysis of the CFTR proband mutation; we retrospectively evaluated the number of cases that had been diagnosed as CFTR-RD based on subsequent symptoms; a second group (353 subjects, group B) performed extensive CFTR molecular analysis in absence of any reported symptoms, followed by a clinical evaluation in cases that carry a second CFTR mutation; we evaluated the number of cases that prospectively were diagnosed as CFTR-RD. Results: We found seven (2.0%) out of 353 subjects of group A and 24 (6.8%) out of 353 subjects of group B as affected by CFTR-RD (chi square, p = 0.002). Conclusions: A percentage of CF carriers are affected by undiagnosed CFTR-RD. Genetic tasting scanning analysis helps to identify CFTR-RD, some of which may benefit from follow-up and specific therapies improving their outcome.

Addressing Uncertainty: The Emergence of the CRMS/CFSPID Diagnostic Category Following Newborn Screening for Cystic Fibrosis

“…Referring to this and other studies, Philip Farrell and colleagues suggested that genetic counseling following CF NBS "may eventually need to include the possibility that heterozygote infants have a higher risk of CFTR-RD conditions" [32,116]. Consistent with this suggestion, Maria Valeria Esposito and colleagues from Italy provided evidence that some CF carriers are living with "undiagnosed CFTR-RD" and suggested that more extensive genetic testing of carriers could help to identify such cases [117]. However, Farrell and colleagues felt that "incidental detection of carrier status in false-positive infants does not yet seem actionable for the child because of the low absolute risks and thus the expectation that most CF heterozygotes will be healthy -at least until later in life" [32].…”

Diagnosing Cystic Fibrosis in the 21st Century—A Complex and Challenging Task

“…Patients with monosymptomatic presentations (pancreatitis, absence of vas deferens, or bronchiectasis), where CFTR dysfunction does not meet CF criteria, are categorized as having CFTR-Related Disorders, conditions resembling CF symptoms [29]. These patients may have residual mutations, severe mutations shared with CF-affected relatives, other severe complex alleles with residual CFTR activity, or non-CF-causing mutations [113]. Given the diversity of CFTR mutations and related disorders, comprehensive molecular screening covering all 27 exons and regulatory regions (5 ′ UTR, 3 ′ UTR, and partially intronic regions) is necessary [97].…”

Current State of Human Gene Therapy: Approved Products and Vectors

“…CFTR, responsible for the monogenic autosomal recessive cystic fibrosis (CF), impacts 1 in 3500 global live births. Maria V. Esposito et al [76] examined 706 CF carriers, revealing undiagnosed CFTR-RD among a subset. Genetic testing scanning analysis aids in CFTR-RD identification, offering potential for tailored follow-up and therapies to enhance outcomes.…”

“…However, functional duplexes in animals can be more variable in structure than in plants, with only short complementary sequence stretches that may contain gaps and mismatches. Specific rules for functional miRNA-target pairing that capture all known functional targets have not been developed to date [11,16,[76][77][78].…”