Yue Han1,2, Hai Cheng1, Shihong Shao3, Yanhua Lang4, Xiangzhong Zhao2, Yi Lin3, Sai Wang1,2, Xiaomeng Shi1,2, Zhiying Liu1,2, Leping Shao5,6. 1. Department of Nephrology, The Affiliated Qingdao Municipal Hospital of Qingdao University, No. 5 Donghai Middle Road, Qingdao, 266071, PR China. 2. Central Laboratory, The Affiliated Hospital of Qingdao University, Qingdao, 266003, PR China. 3. Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao, 266003, PR China. 4. Department of Nursing, The Affiliated Hospital of Qingdao University, Qingdao, 266003, PR China. 5. Department of Nephrology, The Affiliated Qingdao Municipal Hospital of Qingdao University, No. 5 Donghai Middle Road, Qingdao, 266071, PR China. lepingshao@163.com. 6. Central Laboratory, The Affiliated Hospital of Qingdao University, Qingdao, 266003, PR China. lepingshao@163.com.
Abstract
PURPOSE: Analyze the genotype of 42 Chinese patients with Bartter syndrome type 3 (BS3) and investigate their correlation between genotype and phenotype. METHODS: Identify CLCNKB gene variants by the next-generation sequencing and the multiplex ligation-dependent probe amplification (MLPA), and then evaluate their mutation effects according to 2015 American College of Medical Genetics and Genomics (ACMG) standards and guidelines. RESULTS: Thirty-six different variants in CLCNKB gene, including 13 novel ones, were found. The whole gene deletion of CLCNKB gene was the most frequent mutation (40%), and the rate of large deletions is up to 55%. Among 36 variants, six (c.1244T>A, c.1468G>A, c.849_851delCTT, c.359G>T, c.1052G>T, and c.1309G>A) and three (c.228A>C, c.1294_1295TA>CT, and c.1333T>G) variants were classified as "likely pathogenic variants" and "variants with uncertain significance (VUS)," respectively. The other 27 variants were classified as "pathogenic variants". The most common symptoms included: growth retardation (38/42), polydipsia and polyuria (35/42), constipation (31/42), and vomiting (27/42). All patients presented with hypokalemia, hypochloremia, and metabolic alkalosis. The genotype and phenotype association study revealed that who had mutations probably resulting in complete loss of function of both alleles might have severer phenotype. After the treatment that based on indomethacin and potassium chloride, most patients could achieve obvious recovery of growth rate and restoration of hypokalemia. CONCLUSIONS: The present study have found 36 variants of CLCNKB gene, including 13 novel ones, which enrich the human gene mutation database and provide valuable references to diagnosis, treatment, and the genetic counseling of Chinese population.
PURPOSE: Analyze the genotype of 42 Chinese patients with Bartter syndrome type 3 (BS3) and investigate their correlation between genotype and phenotype. METHODS: Identify CLCNKB gene variants by the next-generation sequencing and the multiplex ligation-dependent probe amplification (MLPA), and then evaluate their mutation effects according to 2015 American College of Medical Genetics and Genomics (ACMG) standards and guidelines. RESULTS: Thirty-six different variants in CLCNKB gene, including 13 novel ones, were found. The whole gene deletion of CLCNKB gene was the most frequent mutation (40%), and the rate of large deletions is up to 55%. Among 36 variants, six (c.1244T>A, c.1468G>A, c.849_851delCTT, c.359G>T, c.1052G>T, and c.1309G>A) and three (c.228A>C, c.1294_1295TA>CT, and c.1333T>G) variants were classified as "likely pathogenic variants" and "variants with uncertain significance (VUS)," respectively. The other 27 variants were classified as "pathogenic variants". The most common symptoms included: growth retardation (38/42), polydipsia and polyuria (35/42), constipation (31/42), and vomiting (27/42). All patients presented with hypokalemia, hypochloremia, and metabolic alkalosis. The genotype and phenotype association study revealed that who had mutations probably resulting in complete loss of function of both alleles might have severer phenotype. After the treatment that based on indomethacin and potassium chloride, most patients could achieve obvious recovery of growth rate and restoration of hypokalemia. CONCLUSIONS: The present study have found 36 variants of CLCNKB gene, including 13 novel ones, which enrich the human gene mutation database and provide valuable references to diagnosis, treatment, and the genetic counseling of Chinese population.
Entities:
Keywords:
Bartter syndrome type 3; CLCNKB gene; Genotype; Phenotype