原发性远端肾小管酸中毒患者的基因突变分析和临床表型研究  

Mutation analysis and phenotypic investigation in patients with primary distal renal tubular acidosis

作　　者：郭文聪 董冰子 张瑞晓 刘志英 辛卿 石晓梦 韩玥 郎艳华 赵向忠[4] 蔡琰[1] 尤青青 孙艳[1] 杜华晟 邵乐平[1] Guo Wencong;Dong Bingzi;Zhang Ruixiao;Liu Zhiying;Xin Qing;Shi Xiaomeng;Han Yue;Lang Yanhua;Zhao Xiangzhong;Cai Yan;You Qingqing;Sun Yan;Du Huasheng;Shao Leping(Department of Nephrology,the Affiliated Qingdao Municipal Hospital of Qingdao University,Qingdao 266071,China;Department of Endocrinology,the Affiliated Hospital of Qingdao University,Qingdao 266003,China;Department of Nursing,the Affiliated Hospital of Qingdao University,Qingdao 266003,China;Central Laboratory,the Affiliated Hospital of Qingdao University,Qingdao 266003,China)

机构地区：[1]青岛大学附属市立医院肾内科,青岛266071 [2]青岛大学附属医院内分泌科,青岛266003 [3]青岛大学附属医院护理部,青岛266003 [4]青岛大学附属医院中心实验室,青岛266003

出　　处：《中华肾脏病杂志》2021年第9期712-722,共11页Chinese Journal of Nephrology

基　　金：国家自然科学基金面上项目(81873594)

摘　　要：目的对原发性远端肾小管酸中毒(distal renal tubular acidosis,dRTA)患者进行基因突变分析和基因型-表型相关性研究,以提高对该病的认识和理解。方法通过Sanger测序或全外显子组测序的方法对2010年4月至2020年9月青岛大学附属医院和青岛大学附属市立医院确诊的来自37个家系的44例原发性dRTA患者进行致病基因突变分析,根据2015年美国医学遗传学和基因组学学会(American College of Medical Genetics and Genomics,ACMG)的分类标准和指南评估变异致病性。总结患者的临床特点,并进行基因型和表型的关联研究。结果44例dRTA患者共确定SLC4A1基因7个变异,ATP6V0A4基因17个变异,ATP6V1B1基因15个变异,其中新增11个新变异;根据ACMG指南,39个变异中致病性、可能致病性和良性变异分别为22、16和1个。9例患者是SLC4A1基因突变导致的常染色体显性遗传dRTA,4例患者为SLC4A1基因突变导致的常染色体隐性遗传dRTA合并东南亚卵圆形红细胞增多症并伴有贫血,14例和8例患者分别为ATP6V0A4基因和ATP6V1B1基因突变导致的常染色体隐性遗传dRTA,2例患者不符合常染色体隐性遗传模式仅携带1个ATP6V1B1杂合突变,7例患者检测结果为阴性。43例患者均为完全性dRTA,1例患者为不完全性dRTA。ATP6V0A4基因和ATP6V1B1基因突变导致患者感音神经性耳聋的患病率分别为2/14和6/10。成人、儿童和婴幼儿慢性肾脏病的发生频率分别为4/4、2/4、1/36。经以枸橼酸钾钠合剂为基础的药物治疗后,大部分患儿的生长发育(28/40)和电解质紊乱(41/44)得到明显改善。结论本研究44例原发性dRTA共发现3个致病基因SLC4A1、ATP6V0A4、ATP6V1B1的39个变异位点,其中11个为新变异。dRTA人群基因型和表型密切相关。经恰当的治疗后,大部分患者的病情获得改善。本研究丰富了人类基因突变数据库,将为dRTA人群的遗传咨询和诊治提供有益的借鉴.Objective To analyze the gene variants in patients with primary distal renal tubular acidosis(dRTA),and explore the correlation between the genotype and phenotype.Methods The Sanger direct sequencing or whole-exome sequencing was used to identify causal variants and the variation pathogenicity was evaluated according to 2015 American College of Medical Genetics and Genomics(ACMG)standards and guidelines in 44 dRTA patients(37 families)diagnosed in the Affiliated Qingdao Municipal Hospital of Qingdao University and the Affiliated Hospital of Qingdao University from April 2010 to September 2020.The clinical features of the patients were summarized,and the correlation between the genotype and phenotype was investigated.Results Seven variants of SLC4A1 gene,17 variants of ATP6V0A4 gene,and 15 variants of ATP6V1B1 gene were identified in 44 patients with dRTA,and of which 11 variants were new ones.According to ACMG guidelines,the pathogenic,likely pathogenic,benign variants among the 39 variants were 22,16 and 1,respectively.Nine patients were autosomal dominant hereditary dRTA caused by SLC4A1 gene mutation,4 patients with autosomal recessive hereditary dRTA complicated with Southeast Asian ovalocytosis and anemia were caused by SLC4A1 gene mutation,and 14 patients caused by ATP6V0A4 gene mutation and 8 patients caused by ATP6V1B1 gene mutation were autosomal recessive hereditary dRTA;Two children with dRTA were found to carry one monoallelic defect in ATP6V1B1,and no causal gene mutation was identified in 7 patients.One patient showed incomplete dRTA,and the other 43 patients showed complete dRTA.The prevalence of sensory neural hearing loss caused by ATP6V0A4 and ATP6V1B1 mutation were 2/14 and 6/10 respectively.The frequency of chronic kidney disease in adults,children and infants were 4/4,2/4,and 1/36,separately.After the drug treatment based on potassium citrate and sodium citrate,the growth and development(28/40)and electrolyte disturbance(41/44)of most patients were significantly improved.Conclusions The prese

关 键 词：酸中毒 肾小管性 突变 基因型 表型 SLC4A1基因 ATP6V0A4基因 ATP6V1B1基因 

分 类 号：R692.6[医药卫生—泌尿科学]