Genetic analysis and functional study of novel CFTR variants in Chinese children with cystic fibrosis

To describe the clinical characteristics of Chinese cystic fibrosis (CF) patients and to investigate the variants of CFTR and their potential pathogenicity. Study design Chinese patients with potential CF diagnosis were studied. Clinical data were reviewed retrospectively from medical records. Whole exome sequencing and genetic evaluation was conducted to explore potential gene variants. The disruption of the variants to protein structure and function was explored and validated using in vitro experiments and in silico analysis. Four patients were recruited to the study, three of them were diagnosed as CF, and one was diagnosed as CFTR-related disorder. The age at symptom onset for the patients in this study ranged from newborn to 6 years, while the age at diagnosis varied from 3 to 11 years. All four patients exhibited bilateral diffuse bronchiectasis with Pseudomonas aeruginosa infections, and three of them had malnutrition. Finger clubbing was observed in three patients, two of whom displayed mixed ventilatory dysfunction. The CFTR variants spectrum of Chinese children with CF differs from that of Caucasian. A total of six variants were identified, two of which were first reported (c.1219G>T [p.Glu407*] and c.1367delT [p.Ala457Leufs*12]). The nonsense variants c.1219G>T, c.1657C>T and c.2551C>T and the frameshift variant c.1367delT were predicted to introduce premature stop codon and produce shorten CFTR protein, which was also first validated by in vitro truncation assay in this study. The missense variant c.1810A>C was predicted to disrupt the function of the nucleotide-binding domain 1 (NBD1) in the CFTR protein. The splicing variant c.1766+5G>T caused skipping of exon 13 and damaged the integrity of CFTR protein. Our study expands the spectrum of phenotypes and genotypes for CF of Chinese origin, which differs significantly from that of Caucasian. Genetic analysis and counseling are crucial and deserve extensive popularization for the diagnosis of CF in patients of Chinese origin.