Abstract Individuals with monogenic diseases, even those with identical disease-causing mutations, exhibit considerable clinical heterogeneity in severity and outcomes. In this study, we quantified total and allele-specific transcript levels in nasal brushings from patients diagnosed with cystic fibrosis (CF) who are homozygous or compound heterozygous for variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Among CF patients, total CFTR transcript levels showed greater variability than in non-CF individuals, although both groups exhibited a broad range of transcript expression. Compound heterozygous study subjects also displayed notable differences in allelic dosage, known as allelic skewing. The expression from the non-F508del allele predominated in the total transcript pool. For a small group of patients with nasal brushings available before and after treatment with FDA/EMA-approved drugs Trikafta/Kaftrio (a combination of elexacaftor-tezacaftor-ivacaftor) or Symkevi (a combination of tezacaftor-ivacaftor), we observed no effect on total CFTR transcript abundance but detected changes in allelic expression patterns. These findings reveal important aspects to be considered for personalized therapeutic approaches to CF and other monogenic diseases and emphasize previously unappreciated aspects of mRNA expression during pathogenesis.
Freyberg et al. (Fri,) studied this question.