中文摘要：

目的通过二代测序探讨儿童不明原因门脉高压的遗传病因,以提高临床认识。方法 2012至2016年3月在复旦大学附属金山医院收治的4例不明原因的儿童门脉高压病例,均进行全外显子测序或肝病基因Panel的高通量测序,对临床表现进行回顾性分析。结果 4例患儿中,男1例,女3例,发病年龄3.3-6.4岁。主要临床表现为上消化道出血3例,脾肿大4例,肝肿大2例;肝内胆管扩张1例;转氨酶轻度升高2例。4例患儿影像学上均有肾脏病变,肝脏合成功能和肾功能均正常。二代基因测序及Sanger验证,4例患儿均在PKHD1基因上发现复合杂合突变,其中无义突变和经典剪切位点突变各1个,缺失突变（移码突变）和错义突变（少见位点）各3个。例1外显子32上第4 481位碱基A缺损造成移码突变和外显子51的前1位内含子区碱基G突变为A影响剪切位点;例2外显子24上第2 507位碱基T突变为C,导致第836位上的缬氨酸变为丙氨酸,外显子58上第9 568位碱基C突变为T,导致编码第3 190位谷氨酰胺的密码子变成终止密码子。例3外显子12上第847位碱基T突变为C,导致第283位上的苯丙氨酸转变为亮氨酸,外显子58上第9 455位密码子A缺失导致移码突变。例4外显子61上第10 315位碱基G突变为T,导致第3 429位上的天冬氨酸转变为酪氨酸,外显子27上第3 028至3 039位碱基缺失,并插入AGGT导致移码突变。最终4例患儿均确诊为常染色体隐性遗传性多囊肾病。结论 PKHD1基因突变引起的常染色体隐性遗传性多囊肾病是我国儿童门脉高压的重要病因,二代基因测序是确诊的有效手段。

英文摘要：

Objective Using the next generation sequencing to explore the etiology of Chinese children with portal hypertension,which was hard to be diagnosed by routine examinations.Methods The whole exome sequencing and hepatic panel were used to explore the cause of four children with portal hypertension hospitalized in Jinshan Hospital of Fudan University from 2012 to March2016.The clinical features were summarized retrospectively.Results The patients consisted of one male and three females,and their ages of onset ranged from 3.3 to 6.4 years with average age of 4.65 years.The main clinical features included upper gastrointestinal hemorrhage in three patients,splenomegaly in four patients,hepatomegaly in two patients,intra-hepatic bile duct dilation in one patient,elevation of serum alanine aminotransferase in two patients.Kidney lesions were detected by imaging in all patients,whereas both hepatic synthetic function and kidney function were tested to be normal.Finally,diverse compound heterozygous mutations were identified in PKHD1 gene in all patients by the next generation sequencing and confirmed by Sanger sequencing.The identified PKHD1 gene mutations included one nonsense mutation,one typical splicing site mutation,three deletion mutation induced frameshift mutations,and three rare missense mutations.c.8108-1G〉A and c.4481 del A p.N1494 fs were identified in case1,c.9568C〉T p.Q3190 X and c.2507T〉C p.V836 A were identified in case 2,c.9455 del A p.N3152 fs and c.847T〉C p.F283 L were identified in case 3,c.10315G〉T p.D3439 Y and c.3028-c.3039 del GGAGAAGACCTCins AGGT p.G1010 fs were identified in case4.All four children were diagnosed with autosomal recessive polycystic kidney disease.Conclusion Autosomal recessive polycystic kidney disease is an important cause of noncirrhotic portal hypertension in children,and the next generation sequencing is aneffective method for diagnosis.