钠-牛磺胆酸共转运多肽缺陷患儿的肝功能及基因特点

Liver function and genetic traits of sodium-taurocholate cotransporting polypeptide deficiency in children

目的探讨钠-牛磺胆酸共转运多肽(NTCP)缺陷病患儿的肝功能及基因特点。方法选取经基因测序确诊的NTCP缺陷病患儿(n=11)及其父母(n_(父)=11,n_(母)=11)为研究对象,收集NTCP缺陷病患儿的年龄、出生史、家族史及新生儿期黄疸等一般临床资料;抽取患儿入院治疗前空腹静脉血,检测血清谷丙转氨酶(ALT)、谷草转氨酶(AST)、总胆红素(TBIL)、直接胆红素(DBIL)、间接胆红素(IBIL)及胆汁酸(TBA);抽取患儿及父母外周血采用高通量测序法进行基因检测,对患儿突变基因与其父母基因进行Sanger验证,并运用Rare Exome Variant Ensemble Learner(REVEL)、Sortig Intolerant from Tolerant(SIFT)、PolyPhen-2、Mutationtation Taster、Genomic Evolutionary Rate Profiling(GERP^(+))综合性预测软件对突变位点进行危害预测;随访患儿1年,检测血清ALT、AST、TBA、TBIL、DBTL及IBIL等肝功能指标。结果11例NTCP缺陷病患儿,男6例(54.5%)、女5例(45.4%),确诊年龄40~221d、平均(99.82±69.63)d,血清ALT、AST、TBA、TBIL、DBIL及IBIL升高分别为8例(72.7%)、8例(72.7%)、11例(100%)、6例(54.5%)、7例(63.6%)及4例(36.4%);所有患儿均为SLC10A1基因(c.800C>T)纯合突变,父母为(c.800C>T)突变携带者,除检测到与疾病表型高度相关的SLC10A1基因突变外,还检测到与临床相关性不明确突变位点134个;治疗后患儿随访肝功能指标,除TBA外,其余指标下降良好,随着访时间延长TBA呈现下降趋势。结论NTCP缺陷病患儿肝功能异常以TBA增高为主要特征;SLC10A1基因突变是直接原因,已发现多个突变位点可致病,目前c.800C>T是热点突变,患者可呈杂合或纯合突变。

Objective To examine the liver function and genetic traits in children with sodium-taurocholate cotransporting polypeptide(NTCP)deficiency.Methods Children(n=11)with NTCP deficiency,diagnosed by gene sequencing,and their fathers(n=11)and mothers(n=11)were selected as objects of study.General clinical data such as age,birth history,family history,and neonatal jaundice were collected.Fasting venous blood was collected from the children patients prior to admission to hospital to measure serum alanine transaminase(ALT),aspartate aminotransferase(AST),total bilirubin(TBIL),direct bilirubin(DBIL),indirect bilirubin(IBIL),and bile acid(TBA).The peripheral blood of the children patients and their parents was extracted for gene detection by using high-throughput sequencing.The mutated genes of the children patients and the genes of their parents were verified by Sanger sequencing,and hazard prediction of mutation loci was performed by using the Rare Exome Variant Ensemble Learner(REVEL),Sortig Intolerant from Tolerant(SIFT),PolyPhen-2,Mutationtation Taster,and Genomic Evolutionary Rate Profiling(GERP^(+))comprehensive prediction software.Children patients were followed up for one year and their liver function indicators such as ALT,AST,TBA,TBIL,DBTL,and IBIL were detected.Results There were 6 males(54.5%)and 5 females(45.4%)in the 11 children with NTCP deficiency.The age of diagnosis was from 40 to 221 days,with an average of(99.82±69.63)days.The increase of Serum ALT,AST,TBA,TBIL,DBIL,and IBIL was detected in 8 cases(72.7%),8 cases(72.7%),11 cases(100%),6 cases(54.5%),7 cases(63.6%),and 4 cases(36.4%),respectively.All children patients had a pure mutation in the SLC 10 A 1 gene(c.800C>T)and their parents were carriers of the(c.800C>T)mutation.In addition to the SLC 10 A 1 mutation,which was highly correlated with the disease phenotype,134 mutation loci of unclear clinical relevance were also detected.After treatment,the liver function indicators of the children patients were followed up.These indicators decreased well,except for TBA,which showed a downward trend with the extension of the visit time.Conclusion Increased TBA is the main feature of abnormal liver function in children with NTCP deficiency.Mutations in the SLC 10 A 1 gene are the immediate cause,and multiple mutant loci have been identified as causative.c.800C>T is currently a hot spot mutation,and patients can present heterozygous or pure mutations.