CFTR: p.I1023R is a rare but recurrent disease-causing mutation found in Chinese patients with Cystic Fibrosis

Abstract

Cystic fibrosis (CF [MIM 219700]) is a common autosomal recessive disorder in Caucasians, yet less than 20 Chinese patients with molecularly confirmed CF have been reported in both English and Chinese Biomedical journals. Our department is the only center that offers sweat test in Hong Kong, a city of 7.3 million in southern China. We estimate that the incidence of CF is around 1 in 300,000 live births in Chinese population in Hong Kong. Here, we report 6 unrelated Chinese patients with CF with detailed description of their clinical manifestations. With a molecular approach combining NGS, Sanger sequencing and MLPA, we screened the entire protein coding regions of CFTR and selected deep intronic sites for known disease-causing mutations, deletions and duplications. Molecular diagnosis of 4 patients was confirmed, and interestingly 3 patients were found to carry a missense mutation, p.I1023R (CFTR: NM_000492.3: c.T3068G), reported previously in 2 Taiwanese siblings with CF. All 3 patients inherited the mutation from either parent. Bioinformatics tools predict I1023R is possibly damaging to the protein. The clinical manifestations of patients carrying this recurrent mutation are typical CF features including Pseudomonas aeuroginosa pneumonia, bronchiectasis and meconium ileus. From our search in literature and CFTR mutation database, p.I1023R has not been reported in CF patients of other ethnicities. Furthermore, it is not found in our own exome database (200 exomes), ESP6500 and 1000GP, suggesting a low allele frequency. Linkage analysis is currently underway to study whether I1023R is a founder mutation in Han Chinese. In conclusion, we propose that I1023R is a rare but recurrent disease-causing CFTR mutation important in Chinese CF patients. p.I1023R is not included in the CFTR panel recommended by the ACMG. This finding has implications in the design of mutation panels/ analysis of NGS for molecular diagnosis of CF in Chinese population.