儿童高间接胆红素血症的UGT1A1基因突变谱

UGT1A1 gene mutation spectrum with indirect hyperbilirubinemia in children

目的探讨尿苷二磷酸-葡萄糖醛酸转移酶1A1(UGT1A1)基因突变与儿童高间接胆红素血症表型的相关性。方法回顾性分析2013年7月至2019年11月于南京医科大学附属儿童医院消化科就诊的16例高间接胆红素血症患儿,分为Gilbert综合征(GS)、Crigler-Najjar综合征II型(CNS-II)及UGT1A1基因突变无法解释的高间接胆红素血症组,比较其一般临床资料、基因突变位点信息的差别,并通过t检验分析探讨基因突变谱与胆红素水平的关系。结果16例高间接胆红素血症的患者中,10例为GS,3例为CNS-II,3例为UGT1A1基因突变无法解释的高间接胆红素血症。共检测到6个变异类型,其中c.211G>A占37.5%(6/16),c.1456T>G占62.5%(10/16),TATA占37.5%(6/16);与GS相比,CNS发病较早,且血清总胆红素(t=5.539,P<0.05)及间接胆红素水解(t=5.312,P<0.05)均较高,但两组直接胆红素水平(t=1.223,P>0.05)和发病年龄(t=0.361,P>0.05)差异无统计学意义。UGT1A1基因变异的数量与血清胆红素水平之间无相关性,c.1456T>G纯合突变儿童的血清胆红素水平最高。结论儿童UGT1A1基因常见致病变异依次为c.1456T>G、c.211G>A、TATA,说明这些位点突变与儿童高间接胆红素血症的发生相关,对于儿童高间接胆红素血症病因分析,具有重要指导意义。

Objective To explore the relevancy between the uridine diphosphate-glucuronylgly-cosyltransferase 1A1(UGT1A1)gene mutation and the phenotype of indirect hyperbilirubinemia in children.Methods Sixteen cases with indirect hyperbilirubinemia who visited the Department of Gastroenterology,Children's Hospital of Nanjing Medical University from July 2013 to November 2019 were retrospectively analyzed and were divided into Gilbert syndrome(GS),Crigler-Najjar syndrome type II(CNS-II),and indirect hyperbilirubinemia groups unexplained by UGT1A1 gene mutations.The differences in gene mutation site information and general clinical data were compared.The association between gene mutation spectrum and bilirubin level was explored by t-test analysis.Results Ten of the sixteen cases with indirect hyperbilirubinemia had GS,three had CNS-II,and three had indirect hyperbilirubinemia unexplained by UGT1A1 gene mutations.A total of six mutation types were detected,of which c.211G>A accounted for 37.5%(6/16),c.1456T>G accounted for 62.5%(10/16),and TATA accounted for 37.5%(6/16),respectively.Compared with the GS group,the CNS group had early disease onset incidence,high serum total bilirubin(t=5.539,P<0.05),and indirect bilirubin(t=5.312,P<0.05).However,there was no significant difference in direct bilirubin levels(t=1.223,P>0.05)and age of onset(t=0.3611,P>0.05)between the two groups.There was no significant correlation between the number of UGT1A1 gene mutations and serum bilirubin levels.Children with c.1456T>G homozygous mutations had the highest serum bilirubin levels.Conclusion The common pathogenic variants of the UGT1A1 gene sequence are c.1456T>G,c.211G>A,and TATA,indicating that these site mutations are related to the occurrence of indirect hyperbilirubinemia and have important guiding significance for the etiological analysis of indirect hyperbilirubinemia in children.