Alagille综合征患儿11例临床和遗传学分析

Clinical and genetic analysis of eleven pediatric patients with Alagille syndrome

目的 探讨Alagille综合征患儿的临床和分子遗传学特点.方法 收集并分析2010年8月至2017年3月在暨南大学附属第一医院儿科疑诊Alagille综合征的11例患儿的临床资料.提取所有患儿及其父母的外周血DNA,对2016年3月之前诊治的5例患儿JAG1基因所有外显子及其侧翼序列进行一代测序,其余6例患儿利用高通量基因捕获技术、染色体微阵列分析或全基因组拷贝数变异检测,寻找遗传学病因.结果 11例患儿均确诊为Alagille综合征,共同临床表现为胆汁淤积症,其中1例患儿γ-谷氨酰转肽酶水平正常.9例患儿存在角膜后胚胎环和面容畸形,8例存在心脏缺陷,7例存在脊椎异常,其中1例合并有尺桡骨融合畸形.随访发现9例病情趋向稳定,1例婴儿期死于肝衰竭,1例病情加重.11例患儿中,9例共检测到7种JAG1基因变异类型,其中c.1977G＞A（p.Trp659＊）和c.1106_1107delCC （p.Pro369fs）为新变异;另2例20号染色体分别有3.00 Mb和9.24 Mb的杂合性中间缺失,均含完整的JAG1基因.7例JAG1基因变异和2例包含JAG1基因的染色体中间缺失病例的父母未发现相应变异或缺失,其余2例患儿母亲虽携带相应变异,但缺乏Alagille综合征临床表现.结论 Alagille综合征主要表现为胆汁淤积、角膜后胚胎环、面容畸形、心脏缺陷和脊椎异常,存在临床表现度差异和不完全外显现象.发现JAG1基因变异类型7种和包含该基因的染色体中间缺失2种,其中变异c.1977G＞A（p.Trp659＊）、c.1106_1107delCC（p.Pro369fs）和9.24 Mb的染色体中间缺失均未见文献报道.

Objective To explore the clinical and molecular genetic features of patients with Alagille syndrome （AS）.Methods The clinical data of eleven pediatric patients,who were suspected to have AS at the Department of Pediatrics in the First Affiliated Hospital of Jinan University from August 2010 to March 2017,were collected and analyzed.Genomic DNA was extracted from peripheral blood leukocytes of the patients and their parents.For 5 patients collected before March 2006,all JAG1 exons and their flanking sequences were directly sequenced.For the remaining 6 patients,high-throughput gene capture technology,chromosomal microarray analysis （CMA） and whole-genome copy-number variant（CNV） analysis were utilized,when necessary,to explore the genetic causes.Results All patients had cholestasis.However,the γ-glutamyl transpeptidase （GGT） levels in one patient were normal.Nine patients had posterior embryotoxon and facial malformations.Eight patients displayed heart defects.Seven patients presented with vertebral anomalies and among them,1 patient had sacralization of the cubitus and radius.The condition of nine patients tended to be stabilized on follow-up,but 1 patient died of liver failure in late infancy and 1 got worse.Seven JAG1 variants were detected in 9 out of the 11 AS patients,with c.1977G〉A （p.Trp659＊） and c.1106_1107delCC （p.Pro369fs）being two novel variants.Two heterozygous interstitial deletions of 3.0 Mb and 9.24 Mb in size,respectively,in chromosome 20 were discovered in the remaining 2 patients.Both deletions involved the entire JAG1 gene.De novo origin was unveiled for the detected variants in 7 patients and interstitial deletions in two.Although the mother of 2 patients carried the relevant variant,she did not demonstrate any clinical features of AS.Conclusions With cholestasis,posterior embryotoxon,facial malformations,heart defects and vertebral anomalies being the major manifestations,AS demonstrated variable clinical expressivities and incomplete penetrance.This study identified a total of 7 JAG1 variants as well as 2 interstitial deletions involving this gene,and among them,the variants c.1977G〉A （p.Trp659＊）and c.1106_1107delCC （p.Pro369fs）as well as the 9.24 Mb chromosomal interstitial deletion had not been reported previously.