DISCUSSION
The diagnosis of CF remains very difficult in China, due to inadequate awareness of the disease by Chinese physicians for decades, the inaccessibility of sweat chloride testing facility, as well as atypical clinical manifestations and different genetic spectrum compared to Caucasians[4]. It is well identified that the genotypic spectrum of CF varies widely among different populations based on their geographic and ethnic origins. The most common mutation in the Caucasians is c.1521_1523delCTT(p.F508del), with approximately 70% of patients being heterozygous for this mutation[5]. However, it is quite rarely seen in Asia, especially East Asia. The c.1521_1523delCTT (p.F508del) was only observed in 2 patients of Chinese origin currently (1 child in homozygosity and 1 adult in compound heterozygosity)[6, 7]. No cases have ever been reported in other East Asian countries so far. The parents of the child are both from Kaifeng City, Henan Province, which located in the central region of China. Historically, the Henan Province was ruled by the Mongol armies for 130 years. The Mongol armies were predominantly Mongolian, but they also included a small number of Caucasian. Based on this, we speculate that the origin of the c.1521_1523delCTT (p.F508del) variant in China most likely came from the Mongol armies, which may be due to the intermarriage between Chinese and Caucasians during the colonial period.
The first time the boy presented to us was at his 7 years of age. However, due to the limited sequencing methods at that time, we only detected a c.1521_1523delCTT variant on one allele. With the pathogenic role of deep intron mutations in CF disease are gradually recognized, 4 years later, we found the c.3874-4522A>G variant on the other allele and eventually supplemented the genetic data. The c.3874-4522A>G is a deep intron mutation that has never been reported in Chinese population. Bergougnoux et al [8]reported 10 cases with c.3874-4522A>G and found that c.3874-4522A>G is associated with divergent phenotypes, from milder phenotype including few symptoms, delayed symptom onset and better nutritional state (most of the cases) to typical CF with pancreatic insufficiency (only 1 case). In this report, the c.3874-4522A>G was found in a Chinese boy with severe pulmonary diseases from 2 months early infancy, including progressive bronchiectasis, significant lung function defect, and poor weight gain which suggesting severe phenotype. The phenotypic variability might be contributed to the modifier genes, encoding proteins involved in the defense against pathogens or in splicing regulation, and possibly an age-related exhaustion of the splicing machinery[8].
The estimated median survival age of CF patients, which is close to 50 years today[9], is expected to continue to improve in the future, with the recent advent of CFTR modulator therapies[10]. The major clinical characterization of Chinese individuals with CF was the presence of high frequency of respiratory disease[4]. Meanwhile, many studies demonstrate that progression to end-stage lung disease and death is more rapid in those with chronic P. aeruginosa infection than in those without[11]. Therefore, early eradication ofP. aeruginosa treatment can improve the outcome significantly. We believe CF in China has been underestimated due to the lack of clinical suspicion and the inaccessibility of sweat chloride testing facility, which is the gold standard in diagnosing CF. In patients with unexplained bronchiectasis, meconium ileus, and steatorrhea, CF screening including genetic test need to be performed by Chinese pediatricians.