摘要：
Objective:We aimed to define the comprehensive diagnosis of type Ⅰ Bartter syndrome by analyzing a case with a novel splicing homozygous mutation and to discuss the pathogenic mechanism.Methods:The clinical data of the proband were collected.A Next Generation Sequencing (containing 270 selected related genes,such as SLC12A1,KCNJ1,CLCNKB,BSND CASR and SLC12A3) was performed in the proband.Sanger sequencing was used to validate the mutation in the proband and the family members.Then analyzed the pathogenicity of the mutation.Results:The proband manifested hypokalemic metabolic alkalosis,hyperaldosteronemia,fatigue,polyuria and polydipsia.A novel splicing homozygous mutation c.1786+ 2T＞C in SLC12A1 gene was identified to be the genetic cause of type Ⅰ Bartter syndrome in this family.His father was asymptomatic heterozygous carrier,mother and brother were normal.The mutation had not been reported in dbSNP Database,ClinVar Database,Human Gene Mutation Database,Pubmed and CNKI.PolyPhen-2,SIFT and MutationTaster5 predicted that the mutation was possibly pathogenic.Summarizing the clinical symptoms and genetic results,the proband was diagnosed as type Ⅰ Bartter syndrome and the mutation site c.1786+2T＞C was a novel splicing homozygous pathogenic mutation.Conclusion:This is the first report of a novel splicing homozygous mutation c.1786+ 2T＞C in SLC12A1 gene.This paper not only extends current knowledge of the mutation spectrum of the SLC12A1 gene associated with type Ⅰ Bartter snydrome,but also contributes to the clinical diagnosis and genetic counseling of Bartter syndrome and provides a solid theoretical basis for exploring the pathogenic mechanism.%目的:对Ⅰ型Bartter综合征家系剪切位点纯合突变的临床特点及基因检测结果进行分析,从基因水平上明确该病诊断,并探讨该病的致病机制.方法:收集1例Ⅰ型Bartter综合征患儿及家系临床资料,通过二代基因测序检测含SLC12A1、KCNJ1、CLCNKB、BSND、CASR、SLC12A3等基因在内270个相关基因,用Sanger测序对筛查出来的可能致病突变位点进行家系验证,通过软件及查阅文献对突变位点致病性进行分析.结果:先证者临床表现为消瘦乏力、多饮多尿、生长发育落后、低血钾、代谢性碱中毒及高醛固酮血症,测序结果显示:SLC12A1基因c.1786+ 2T＞C剪切位点纯合突变,其父为无症状杂合突变携带者,其母和哥哥未发现变异.查阅文献发现先证者临床表现符合Bartter综合征且SLC12A1基因为Ⅰ型Bartter综合征的致病基因,检索dbSNP数据库、ClinVar数据库、HGMD数据库、Pubmed、中国知网等国内外文献数据库均未发现该突变位点报道.同时,PolyPhen-2、SIFT和MutationTaster 5软件分析预测该突变可能为致病性突变.综合分析临床表型和基因结果该先证者可诊断为Ⅰ型Bartter综合征,且其c.1786+2T＞C剪切位点纯合突变为新发致病性突变.结论:本文首次报道c.1786 +2T＞C突变为新发致病性剪切位点纯合突变,扩展了SLC12A1基因突变谱,为Bartter综合征的临床诊断和遗传咨询提供帮助,并为进一步探索其致病机制提供一定的理论基础.
