Clinical characterization and diagnosis of cystic fibrosis through exome sequencing in Chinese infants with Bartter-syndrome-like hypokalemia alkalosis

Abstract

Cystic fibrosis (CF) is a fatal autosomal-recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. CF is characterized by recurrent pulmonary infection with obstructive pulmonary disease. CF is common in the Caucasian population but is rare in the Chinese population. The symptoms of early-stage CF are often untypical and may sometimes manifest as Bartter syndrome (BS)-like hypokalemic alkalosis. Therefore, the ability of doctors to differentiate CF from BS-like hypokalemic alkalosis in Chinese infants is a great challenge in the timely and accurate diagnosis of CF. In China, sporadic CF has not been diagnosed in children younger than three years of age to date. Three infants, who were initially admitted to our hospital over the period of June 2013 to September 2014 with BS-like hypokalemic alkalosis, were diagnosed with CF through exome sequencing and sweat chloride measurement. The compound heterozygous mutations of the CFTR gene were detected in two infants, and a homozygous missense mutation was found in one infant. Among the six identified mutations, two are novel point mutations (c.1526G>C and c.3062C>T) that are possibly pathogenic. The three infants are the youngest Chinese patients to have been diagnosed with sporadic CF at a very early stage. Follow-up examination showed that all of the cases remained symptom-free after early intervention, indicating the potential benefit of very early diagnosis and timely intervention in children with CF. Our results demonstrate the necessity of distinguishing CF from BS in Chinese infants with hypokalemic alkalosis and the significant diagnostic value of powerful exome sequencing for rare genetic diseases. Furthermore, our findings expand the CFTR mutation spectrum associated with CF.

Keywords

cystic fibrosis / pseudo-Bartter syndrome / hypokalemic alkalosis / CFTR gene / mutations / infants / diagnosis

References

[1] Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahel R, Grzelczak Z, Zielenski J, Lok S, Plavsic N, Chou JL, . Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 1989; 245(4922): 1066–1073

[2] Dawson KP, Frossard PM. The geographic distribution of cystic fibrosis mutations gives clues about population origins. Eur J Pediatr 2000; 159(7): 496–499

[3] Yamashiro Y, Shimizu T, Oguchi S, Shioya T, Nagata S, Ohtsuka Y. The estimated incidence of cystic fibrosis in Japan. J Pediatr Gastroenterol Nutr 1997; 24(5): 544–547

[4] Shen Y, Liu J, Zhong L, Mogayzel PJ Jr, Zeitlin PL, Sosnay PR, Zhao S. Clinical phenotypes and genotypic spectrum of cystic fibrosis in Chinese children. J Pediatr 2016; 171:269–276.e1

[5] Xu BP, Wang H, Zhao YH, Liu J, Yao Y, Feng XL, Shen KL. Molecular diagnosis of two Chinese cystic fibrosis children and literature review. Chin J Pediatr (Zhonghua Er Ke Za Zhi) 2016; 54(5): 344–348 (in Chinese)

[6] Xie Y, Huang X, Liang Y, Xu L, Pei Y, Cheng Y, Zhang L, Tang W. A new compound heterozygous CFTR mutation in a Chinese family with cystic fibrosis. Clin Respir J2017; 11(6):696–702

[7] Wang PL, Jing JY, Shen HH. Retrospective analysis on twenty Chinese cases of cystic fibrosis. Chin J Pediatr (Zhonghua Er Ke Za Zhi) 2008; 46(8): 634–636 (in Chinese)

[8] Macek M Jr, Mercier B, Macková A, Miller PW, Hamosh A, Férec C, Cutting GR. Sensitivity of the denaturing gradient gel electrophoresis technique in detection of known mutations and novel Asian mutations in the CFTR gene. Hum Mutat 1997; 9(2): 36–47

[9] Chen HJ, Lin SP, Lee HC, Chen CP, Chiu NC, Hung HY, Chern SR, Chuang CK. Cystic fibrosis with homozygous R553X mutation in a Taiwanese child. J Hum Genet 2005; 50(12): 674–678

[10] Wagner JA, Vassilakis A, Yee K, Li M, Hurlock G, Krouse ME, Moss RB, Wine JJ. Two novel mutations in a cystic fibrosis patient of Chinese origin. Hum Genet 1999; 104(6): 511–515

[11] Tian X, Liu Y, Yang J, Wang H, Liu T, Xu W, Li X, Zhu Y, Xu KF, Zhang X. p.G970D is the most frequent CFTR mutation in Chinese patients with cystic fibrosis. Hum Genome Var 2016; 3: 15063

[12] Liu JR, Peng Y, Zhao YH, Wang W, Guo Y, He JX, Zhao SY, Jiang ZF. Clinical manifestations and gene analysis of 2 Chinese children with cystic fibrosis. Chin J Pediatr (Zhonghua Er Ke Za Zhi) 2012; 50(11): 829–833 (in Chinese)

[13] Li N, Pei P, Bu DF, He B, Wang GF. A novel CFTR mutation found in a Chinese patient with cystic fibrosis. Chin Med J (Engl) 2006; 119(2): 103–109

[14] Li N, He B, Wang GF, Tang XY. A case report of cystic fibrosis and review of 16 cases of cystic fibrosis in Chinese patients. Chin J Tuberc Respir Dis (Zhonghua Jie He He Hu Xi Za Zhi) 2003; 26(9): 559–562 (in Chinese)

[15] Li HX, Mao WJ, Chen JY, Zheng MF, Ye SG, He YJ, Liu F. Analysis of curative effect of pulmonary lobectomy on atelectasis after lung transplantation. Organ Transplant (Qi Guan Yi Zhi), 2014. 5(1): 24–27, 31 (in Chinese)

[16] Liu Y, Wang L, Tian X, Xu KF, Xu W, Li X, Yue C, Zhang P, Xiao Y, Zhang X. Characterization of gene mutations and phenotypes of cystic fibrosis in Chinese patients. Respirology 2015; 20(2): 312–318

[17] Cremonesi L, Ferrari M, Belloni E, Magnani C, Seia M, Ronchetto P, Rady M, Russo MP, Romeo G, Devoto M. Four new mutations of the CFTR gene (541delC, R347H, R352Q, E585X) detected by DGGE analysis in Italian CF patients, associated with different clinical phenotypes. Hum Mutat 1992; 1(4): 314–319

[18] Lee KH, Ryu JK, Yoon WJ, Lee JK, Kim YT, Yoon YB. Mutation analysis of SPINK1 and CFTR gene in Korean patients with alcoholic chronic pancreatitis. Dig Dis Sci 2005; 50(10): 1852–1856

[19] Sheppard DN, Travis SM, Ishihara H, Welsh MJ. Contribution of proline residues in the membrane-spanning domains of cystic fibrosis transmembrane conductance regulator to chloride channel function. J Biol Chem 1996; 271(25): 14995–15001

[20] Rodríguez-Soriano J. Bartter and related syndromes: the puzzle is almost solved. Pediatr Nephrol 1998; 12(4): 315–327

[21] Kessler WR, Andersen DH. Heat prostration in fibrocystic disease of the pancreas and other conditions. Pediatrics 1951; 8(5): 648–656

[22] Scurati-Manzoni E, Fossali EF, Agostoni C, Riva E, Simonetti GD, Zanolari-Calderari M, Bianchetti MG, Lava SA. Electrolyte abnormalities in cystic fibrosis: systematic review of the literature. Pediatr Nephrol 2014; 29(6): 1015–1023

[23] Luke RG, Galla JH. It is chloride depletion alkalosis, not contraction alkalosis. J Am Soc Nephrol 2012; 23(2): 204–207

[24] Mei-Zahav M, Durie P, Zielenski J, Solomon M, Tullis E, Tsui LC, Corey M. The prevalence and clinical characteristics of cystic fibrosis in South Asian Canadian immigrants. Arch Dis Child 2005; 90(7): 675–679

[25] Callaghan BD, Hoo AF, Dinwiddie R, Balfour-Lynn IM, Carr SB. Growth and lung function in Asian patients with cystic fibrosis. Arch Dis Child 2005; 90(10): 1029–1032

[26] Mattar AC, Leone C, Rodrigues JC, Adde FV. Sweat conductivity: an accurate diagnostic test for cystic fibrosis? J Cyst Fibros 2014; 13(5): 528–533

[27] Farrell PM, White TB, Ren CL, Hempstead SE, Accurso F, Derichs N, Howenstine M, McColley SA, Rock M, Rosenfeld M, Sermet-Gaudelus I, Southern KW, Marshall BC, Sosnay PR. Diagnosis of cystic fibrosis: consensus guidelines from the Cystic Fibrosis Foundation. J Pediatr 2017; 181S: S4–S15.e1

Acknowledgements

We thank Ms. Li Wang for her help with analyzing the sequencing results.

Compliance with ethics guidelines

Liru Qiu, Fengjie Yang, Yonghua He, Huiqing Yuan, and Jianhua Zhou declare no conflicts of interests. All procedures were followed in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all of the parents or legal guardians of the patients included in the study. This article does not contain any studies with animal subjects performed by any of the authors.

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