CFTR: I1023R is a rare but recurrent disease-causing mutation found in Chinese patients with cystic fibrosis

Oral Free Paper SessionOutstanding Oral PresentationBackground: Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the gene CFTR. CF is a common in Caucasians, yet less than twenty Chinese patients with molecular confirmation have been reported. Our department is the only center that offers sweat test in Hong Kong, and from our data we estimate the incidence of CF as 1 in 300,000 in local Chinese. We report the findings of a comprehensive genetic analysis of 6 unrelated Chinese patients with the clinical suspicion of CF. Methods and results: Using NGS (next generation sequencing), Sanger sequencing and MLPA (multiplex ligationdependent probe amplification), we screened for single nucleotide variations and deletion/ duplications in all exons and three intronic hotspots of CFTR gene. Molecular diagnosis was confirmed in four unrelated patients. Importantly, three inherited the same missense mutation, I1023R (CFTR: NM_000492.3: c.T3068G), which was reported only in two Taiwanese siblings with CF but not in patients of other ethnicities. Patients with this recurrent mutation have typical CF features, including Pseudomonas aeuroginosa pneumonia, bronchiectasis and meconium ileus. It is not found in our in-house database of 200 exomes, or public databases like ESP6500 and 1000GP, indicating a very low allelic frequency. Using linkage and functional analysis, we showed that I1023R is likely a founder mutation in Hans Chinese and the mutant CFTR protein is potentially having a post-translational defect, resulting in reduced expression compared with the wild-type protein. Conclusion: We have summarized the diagnosis of all reported CF patients in the last twenty years. In addition to our genetic analysis of local patients, we propose that I1023R is a rare but recurrent, potential founder type disease-causing CFTR mutation in Chinese CF patients. Currently I1023R is not a screening target in the cystic fibrosis mutation panel (i.e. ACMG25) which includes the core mutations recommended by American College of Medical Genetics (ACMG). This finding has implications in the design of mutation panels, and analysis of NGS for molecular diagnosis of CF for Chinese patients