Cystic fibrosis genetics: from molecular understanding to clinical application

Abstract

Investigation of disease-causing variants such as F508del is resolving the mechanisms underlying cystic fibrosis transmembrane conductance regulator (CFTR) folding and will inform rational design of compounds to correct the folding of mutant CFTR. New tissue culture methods will facilitate the evaluation of molecular targeted therapy for a wide array of CFTR genotypes, and new animal models should enable assessment of treatment at the earliest stages of the disease. Analyses of affected twin and sibling pairs have quantified the contribution of genetic and non-genetic modifiers to variation in key features of cystic fibrosis. Candidate and genome-wide approaches have identified biologically plausible gene modifiers of lung disease severity, neonatal intestinal obstruction and diabetes in cystic fibrosis. Annotation of variants in CFTR will increase the utility of genetic testing in newborn screening, carrier testing and diagnostic settings. Assignment of variants as disease-causing will validate efforts to target variants for molecular therapies. Small-molecule therapy for cystic fibrosis has been successful for patients carrying a subset of CFTR variants. Grouping of variants according to responses in cell-based assays (that is, theratypes) could expedite treatment of affected individuals with rare CFTR genotypes.