Citrin缺陷致婴儿肝内胆汁淤积症的临床和基因变异分析

Analysis of clinical and genetic variation in neonatal intrahepatic cholestasis caused by citrin deficiency

目的探讨Citrin缺陷致婴儿肝内胆汁淤积症(NICCD)患儿的临床表型和基因变异情况, 为家系的遗传咨询和临床诊治提供依据。方法以2019年2月至2021年3月期间在郑州大学附属儿童医院就诊的11例胆汁淤积症患儿作为研究对象, 应用高通量测序技术检测11例患儿的基因变异情况, 100名正常人作为对照。利用Sanger测序和QPCR技术对可疑位点和家系成员进行验证。结果 11例NICCD患儿均有不同程度的黄疸和肝损害症状, 合并凝血功能障碍和贫血(n = 7), 心脏畸形(n = 2), 心肌酶高(n = 4), 高酯血症(n = 1), 高钾血症(n = 1),迁延性腹泻(n = 3), 发育迟滞(n = 1)。11例患儿共检测到10种不同类型的SLC25A13基因突变, 包括3种移码突变, 2种剪切改变, 2种错义突变, 1种内含子插入, 1种无义突变, 1种杂合缺失。经查阅迄今文献和数据库, c.1878delG(p.I627Sfs*73), exon11缺失尚未见报道。结论 NICCD临床特征无特异性, 基因检测有助于该病的早期精准诊断, 为临床治疗和家系成员的遗传咨询提供重要依据。新变异位点的检出丰富了SLC25A13基因变异谱。

ObjectiveTo investigate the clinical phenotype and gene variation conditions in neonatal intrahepatic cholestasis caused by citrin deficiency(NICCD),so as to provide a basis for genetic counseling and clinical diagnosis and treatment of the family.Methods s11 cases of neonatal intrahepatic cholestasis who visited the Children's Hospital Affiliated to Zhengzhou University between February 2019 and March 2021 were selected as the study subjects.High-throughput sequencing technology was used to detect the gene variation condition in 11 neonatal patients and 100 normal control neonates.The suspicious loci and family members were verified by Sanger sequencing and QPCR technology.Results All 1l children with NICCD had different degrees of jaundice and liver damage symptoms,combined with coagulation dysfunction and anemia(n=7),cardiac malformation(n=2),elevated myocardial enzymes(n=4),hyperlipidemia(n=1),hyperkalemia(n=1),persistent diarrhea(n=3),developmental delay(n=1).A total of 10 different types of SLC25A/3 gene mutations were detected in 11 cases,including three frameshift mutations,two splicing changes,two missense mutations,one intron insertion,one nonsense mutation,and one heterozygous deletion.After reviewing literature and databases,c.1878delG(p.1627Sfs*73)and exon11 deletion were novel mutations that had not been reported at home or abroad.Conclusion The clinical features of NICCD are non-specific,and genetic testing aids in the early and accurate diagnosis of the disease,providing an important basis for clinical treatment and genetic counseling for family members.In addition,the detection of novel mutation sites has enriched the SLC25A13 gene variation spectrum.