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婴儿肝内胆汁淤积症患儿的临床特征及基因分析
王美娟, 钟雪梅, 马昕, 宁慧娟, 朱丹, 宫幼喆, 金萌
中国当代儿科杂志 ›› 2021, Vol. 23 ›› Issue (1) : 91-97.
PDF(1697 KB)
PDF(1697 KB)
婴儿肝内胆汁淤积症患儿的临床特征及基因分析
Clinical characteristics and gene variants of patients with infantile intrahepatic cholestasis
目的 分析婴儿肝内胆汁淤积症患儿的临床资料及基因变异特点。方法 收集2017年6月至2019年6月于首都儿科研究所附属儿童医院消化内科就诊的疑似遗传代谢性婴儿肝内胆汁淤积症患儿的临床资料，采用目标基因捕获结合高通量测序技术进行基因检测，并进行Sanger验证。结果 共纳入40例患儿，13例（32%）患儿发现致病基因，包括3例SLC25A13基因突变导致的希特林蛋白缺乏症，3例JAG1基因突变导致的Alagille综合征，3例ABCB11基因突变导致的进行性家族性肝内胆汁淤积症2型，1例HSD3B7基因突变导致的先天性胆汁酸合成障碍1型，1例AKR1D1基因突变导致的先天性胆汁酸合成障碍2型，1例NPC1基因突变导致的尼曼匹克病，1例CFTR基因突变导致的囊性纤维化。结论 婴儿肝内胆汁淤积症病因繁多，高通量测序技术对临床疑似遗传代谢病的肝内胆汁淤积症患儿的诊断有重要价值。
Objective To explore the clinical characteristics and genetic findings of patients with infantile intrahepatic cholestasis. Methods The clinical data were collected in children who were admitted to the Department of Gastroenterology in Children's Hospital, Capital Institute of Pediatrics from June 2017 to June 2019 and were suspected of inherited metabolic diseases. Next generation sequencing based on target gene panel was used for gene analysis in these children. Sanger sequencing technology was used to verify the genes of the members in this family. Results Forty patients were enrolled. Pathogenic gene variants were identified in 13 patients (32%), including SLC25A13 gene variation in 3 patients who were diagnosed with citrin deficiency, JAG1 gene variation in 3 patients who were diagnosed with Alagille syndrome, ABCB11 gene variation in 3 patients who were diagnosed with progressive familial intrahepatic cholestasis type 2, HSD3B7 gene variation in 1 patient who was diagnosed with congenital bile acid synthesis defect type 1, AKR1D1 gene variation in 1 patient who was diagnosed with congenital bile acid synthesis defect type 1, NPC1 gene variation in 1 patient who was diagnosed with Niemann-Pick disease, and CFTR gene variation in 1 patient who was diagnosed with cystic fibrosis. Conclusions The etiology of infantile intrahepatic cholestasis is complex. Next generation sequencing is helpful in the diagnosis of infantile intrahepatic cholestasis.
Infantile intrahepatic cholestasis / Gene / Next generation sequencing / Child
[1] Fischler B, Lamireau T. Cholestasis in the newborn and infant[J]. Clin Res Hepatol Gastroenterol, 2014, 38(3):263-267.
[2] Togawa T, Sugiura T, Ito K, et al. Molecular genetic dissection and neonatal/infantile intrahepatic cholestasis using targeted next-generation sequencing[J]. J Pediatr, 2016, 171:171-177.e4.
[3] Nicastro E, Di Giorgio A, Marchetti D, et al. Diagnostic yield of an algorithm for neonatal and infantile cholestasis integrating next-generation sequencing[J]. J Pediatr, 2019, 211:54-62.e4.
[4] Lipiński P, Ciara E, Jurkiewicz D, et al. Targeted next-generation sequencing in diagnostic approach to monogenic cholestatic liver disorders-single-center experience[J]. Front Pediatr, 2020, 8:414.
[5] Moyer V, Freese DK, Whitington PF, et al. Guideline for the evaluation of cholestatic jaundice in infants:recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition[J]. J Pediatr Gastroenterol Nutr, 2004, 39(2):115-128.
[6] Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants:a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]. Genet Med, 2015, 17(5):405-424.
[7] Okano Y, Ohura T, Sakamoto O, et al. Current treatment for citrin deficiency during NICCD and adaptation/compensation stages:strategy to prevent CTLN2[J]. Mol Genet Metab, 2019, 127(3):175-183.
[8] Lipiński P, Jurkiewicz D, Ciara E, et al. Neonatal cholestasis due to citrin deficiency:diagnostic pitfalls[J]. Acta Biochim Pol, 2020, 67(2):225-228.
[9] Dimmock D, Maranda B, Dionisi-Vici C, et al. Citrin deficiency, a perplexing global disorder[J]. Mol Genet Metab, 2009, 96(1):44-49.
[10] Abuduxikuer K, Chen R, Wang ZL, et al. Risk factors associated with mortality in neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) and clinical implications[J]. BMC Pediatr, 2019, 19(1):18.
[11] Zhang ZH, Lin WX, Zheng QQ, et al. Molecular diagnosis of citrin deficiency in an infant with intrahepatic cholestasis:identification of a 21.7kb gross deletion that completely silences the transcriptional and translational expression of the affected SLC25A13 allele[J]. Oncotarget, 2017, 8(50):87182-87193.
[12] Kamath BM, Baker A, Houwen R, et al. Systematic review:the epidemiology, natural history, and burden of alagille syndrome[J]. J Pediatr Gastroenterol Nutr, 2018, 67(2):148-156.
[13] Guegan K, Stals K, Day M, et al. JAG1 mutations are found in approximately one third of patients presenting with only one or two clinical features of Alagille syndrome[J]. Clin Genet, 2012, 82(1):33-40.
[14] 郭丽, 赵书涛, 程映, 等. Alagille综合征患儿11例临床和遗传学分析[J]. 中华儿科杂志, 2018, 56(5):353-358.
[15] Gilbert MA, Bauer RC, Rajagopalan R, et al. Alagille syndrome mutation update:comprehensive overview of JAG1 and NOTCH2 mutation frequencies and insight into missense variant classification[J]. Hum Mutat, 2019, 40(12):2197-2220.
[16] 王建设, 李丽婷. 家族性肝内胆汁淤积症的研究进展[J]. 中华实用儿科临床杂志, 2018, 33(19):1451-1454.
[17] Shah I, Chilkar S. Progressive familial intrahepatic cholestasis type 2 in an Indian child[J]. J Pediatr Genet, 2017, 6(2):126-127.
[18] Wang HH, Wen FQ, Dai DL, et al. Infant cholestasis patient with a novel missense mutation in the AKR1D1 gene successfully treated by early adequate supplementation with chenodeoxycholic acid:a case report and review of the literature[J]. World J Gastroenterol, 2018, 24(35):4086-4092.
[19] Kamal N, Surana P, Koh C. Liver disease in patients with cystic fibrosis[J]. Curr Opin Gastroenterol, 2018, 34(3):146-151.
[20] Eminoglu TF, Polat E, Gökçe S, et al. Cystic fibrosis presenting with neonatal cholestasis simulating biliary atresia in a patient with a novel mutation[J]. Indian J Pediatr, 2013, 80(6):502-504.
北京市医院管理中心2018年度消化内科学科协同发展中心重点项目遗传代谢性肝病临床诊疗研究体系平台建设（XXZ0505）。
