Molecular Genetic Dissection and Neonatal/Infantile Intrahepatic Cholestasis Using Targeted Next-Generation Sequencing
Molecular Genetic Dissection and Neonatal/Infantile Intrahepatic Cholestasis Using Targeted Next-Generation Sequencing
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DOI：
10.1016/j.jpeds.2016.01.006
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发表时间：
2016-04-01
影响因子：
5.1
通讯作者：
Saitoh, Shinji
中科院分区：
文献类型：
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作者：
Togawa, Takao;Sugiura, Tokio;Saitoh, Shinji
目的通过使用下一代测序技术（NGS）确定新生儿/婴儿肝内胆汁淤积症（NIIC）患者的分子遗传学诊断，并进行基因型-表型相关性研究设计：我们招募了没有明确分子遗传学诊断的NIIC患者。我们开发了18个基因的诊断定制面板，并通过NGS对扩增子文库进行测序。然后，我们比较了临床资料之间的分子遗传学证实的受试者与NIIC.Results我们分析了109例NIIC（“遗传性胆汁淤积，”31例;“未知并发症”，如早产，46例;“未知无并发症，”32例），和28例（26%）的分子遗传学诊断。在“遗传性胆汁淤积”组中，每种类型的阳性分子遗传学诊断率为22/31（71%），“未知并发症”组为2/46（4.3%），“未知无并发症”组为4/32（12.5%）。遗传性胆汁淤积组的分子诊断分组如下：Alagille综合征12例，新生儿Dubin-Johnson综合征5例，Citrin缺乏引起的新生儿肝内胆汁淤积症5例，进行性家族性肝内胆汁淤积症或良性复发性肝内胆汁淤积症伴低γ-谷氨酰转肽酶水平6例。几个临床数据，包括发病年龄，直接胆红素，和转氨酶，有显着差异的疾病之间使用分子遗传学diagnosis.Conclusion靶向NGS可用于分子遗传学诊断与NIIC受试者。临床诊断应根据分子遗传学结果重新定义。
Objectives To ascertain a molecular genetic diagnosis for subjects with neonatal/infantile intrahepatic cholestasis (NIIC) by the use of next-generation sequencing (NGS) and to perform a genotype-phenotype correlation.Study design We recruited Japanese subjects with NIIC who had no definitive molecular genetic diagnosis. We developed a diagnostic custom panel of 18 genes, and the amplicon library was sequenced via NGS. We then compared clinical data between the molecular genetically confirmed subjects with NIIC.Results We analyzed 109 patients with NIIC ("genetic cholestasis," 31 subjects; "unknown with complications" such as prematurity, 46 subjects; "unknown without complications," 32 subjects), and a molecular genetic diagnosis was made for 28 subjects (26%). The rate of positive molecular genetic diagnosis in each category was 22 of 31 (71%) for the "genetic cholestasis" group, 2 of 46 (4.3%) for the "unknown with complications" group, and 4 of 32 (12.5%) for the "unknown without complications" group. The grouping of the molecular diagnoses in the group with genetic cholestasis was as follows: 12 with Alagille syndrome, 5 with neonatal Dubin-Johnson syndrome, 5 with neonatal intrahepatic cholestasis caused by citrin deficiency, and 6 with progressive familial intrahepatic cholestasis or benign recurrent intrahepatic cholestasis with low gamma-glutamyl transpeptidase levels. Several clinical datasets, including age of onset, direct bilirubin, and aminotransferases, were significantly different between the disorders confirmed using molecular genetic diagnosis.Conclusion Targeted NGS can be used for molecular genetic diagnosis in subjects with NIIC. Clinical diagnosis should be accordingly redefined in the view of molecular genetic findings.