A Chinese pediatric cystic fibrosis patient with the c.1624G>T, p. Gly542x/c.223C>T, p. Arg75x genotype

We read with great interest the article entitled “A systematic review of the clinical and genetic characteristics of Chinese patients with cystic fibrosis” by Ruihe Shi and colleagues (year 2020, volume 55, issue 11). The authors reported that common CFTR gene mutations, such as c.1624G>T, c.1652G>A, and c.350G>A, had not been reported in China.1 Cystic fibrosis (CF) is an autosomal recessive inherited disease affecting multiple body systems.2 In CF patients, the gene encoding a protein called the cystic fibrosis transmembrane conductance regulator (CFTR) is mutant. This may lead to thick dehydrated mucus secretions in several organ systems (especially the airways), causing progressive infection and damage to the lungs, and shortening the life expectancy of CF patients.3 Here, we report a case of a Chinese CF child with gene mutations of c.1624G>T, p. Gly542x (heterozygous mutation, paternal) and c.223C>T, p. Arg75x (heterozygous mutation, maternal) (Figure 1). This 5-year-old female patient presented with chronic cough, expectoration, wheezing, and growth retardation since the age of 3. Due to recurrent pulmonary infection and repeated dyspnea, she was hospitalized approximately two times every year. During her first admission to our hospital (The Children's Hospital of Nanjing Medical University) when she was 33 months old, sputum culture was positive for Pseudomonas aeruginosa. On the ninth day of hospitalization, she suffered from abdominal distension, weakened bowel sounds, and failure to pass flatus or bowel movements for 3 days without obvious peritonitis. Abdominal computed tomography showed that the colon was narrow, and part of the colon wall was thickened; liver density was generally decreased. The surgery was performed given the diagnosis of Hirschsprung's disease. Human whole-exome sequencing was conducted by Beijing Quanpu Medical Laboratory on the 23rd day of admission. On April 13, 2022, during her third admission to our hospital when she was 46 months old due to aggravated cough and wheezing, along with the gene mutations of c.1624G>T, p. Gly542x and c.223C>T, p. Arg75x, the diagnosis of cystic fibrosis was made. Sputum and bronchoalveolar lavage fluid cultures were consistently positive for P. aeruginosa; aztreonam was administered as an anti-infective. Serum vitamin examination did not show liposoluble vitamin deficiency at that time. Since tobramycin inhalation was not available in our country, she was prescribed oral cefixime and azithromycin, and hypertonic saline for inhalation on her discharge. During the most recent admission, she presented with malnutrition (weight <25th centile) and chronic diarrhea. Serum vitamin examination showed liposoluble vitamin deficiency; consequently, she needed supplementation of liposoluble vitamins and pancreatic enzyme replacement therapy. Increased secretions were seen under a bronchoscopy. Sputum culture was positive for both Staphylococcus aureus and P. aeruginosa, while bronchoalveolar lavage fluid culture was only positive for S. aureus. At present, according to drug sensitivity results, linezolid plus piperacillin-tazobactam were prescribed for antibacterial treatment. Mutations in CFTR, the gene encoding the epithelial ion channel that normally transports chloride and bicarbonate, lead to impaired mucus hydration and clearance.2 Despite the relatively high morbidity in White patients, it is still an extremely rare disease in China. At present, about 200 CF patients have been reported in China; however, no population-based prevalence was calculated.4 The number of CF patients is largely underestimated because many CF patients in China have been misdiagnosed or have missed being diagnosed. A recent study revealed that the prevalence of Chinese CF ranged from 1/153,825 to 1/110,127.5 The most common CFTR gene mutations in Chinese CF patients, which presented with c.2909G→A, are different from those in White patients.1 However, the child in our report carried a common gene mutation among White patients but rare among Chinese patients. Pathogenic mutations in CFTR have conventionally been categorized into classes I–VI according to defects in the protein production process.2 Gene mutation of c.1624G>T, p. Gly542x, which belongs to class I mutations, results in the production of no full-length proteins, and many of these proteins are premature truncation codons leading to short, unstable messenger RNA and absence of full-length CFTR proteins. Patients with this gene mutation may present with recurrent or chronic bacterial and fungal infections, bronchiectasis, pneumothorax, hemoptysis, and respiratory failure. By searching the CFTR2 database (http://www.cftr2.org), we found that there were only four patients with this variant combination in the CFTR2 database and this variant combination may be able to cause pancreatic insufficiency. She experienced colostomy due to neonatal megacolon, and surgery for meconium ileus. Although her clinical manifestations were typical for CF, without sufficient understanding of this disease and newborn screening, the age at CF diagnosis is relatively older. Sweat testing, done in an accredited clinical laboratory, is an important and accurate method for detecting CF, in which the chloride ion concentration is usually higher than 60 mmol/L; however, we did not find an institution that could perform this test during her first admission in our hospital. Since biallelic pathogenic variants of CFTR are the basis for the diagnosis of CF,2, 4 and institutions qualified for this test are very few in China, this patient did not perform sweat chloride detection yet. The population-specific genetic spectrum of CF is still unknown, and CF prevalence would be significantly underestimated in Chinese if using the White-specific screening panel. Thus, the recent study recommended the 53 pathogenic/likely pathogenic variants as CF screening panel for the Chinese population, especially the six variants with high allele frequencies: G970D (c.2909G>A), D979A (c.2936A>C), M469V (c.1405A>G), G622D (c.1865G>A), L88X (c.263T>G), and 1898+5G->T (c.1766+5G>T), which could also be used in clinical diagnosis process.4 Besides, in a most recent systematic review of gene mutations of Chinese CF patients, c.1624G>T was not reported as well.6 To the best of our knowledge, this is the first report of c.1624G>T mutation among Chinese CF patients and this gene mutation would be complementary for CFTR gene mutation data of the Chinese CF population and provide information for the Chinese-specific screening panel. In conclusion, we present this case to complement the CFTR gene pool of the Chinese population with cystic fibrosis and improve clinicians' understanding of this disease in China. Besides, with the development of molecular biology technology, gene detection was expected to play an important role in the early diagnosis, early treatment, and prognosis improvement of the disease. Rui Zhang: Conceptualization; writing—original draft; data curation. Yao Sun: Conceptualization; writing—review and editing; validation. This study did not receive any funding. The authors declare no conflict of interest. The data used and/or analyzed during the current study are available within the manuscript.