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中国循证儿科杂志

中国循证儿科杂志 ›› 2017, Vol. 12 ›› Issue (4): 278-283.

• 论著 • 上一篇    下一篇

基于全外显子组测序对病因不明致死性胎儿水肿遗传学病因的初步分析

殷荣1），杨琳2），胡黎园1），周文浩2）   

  1. 复旦大学附属儿科医院 上海，201102；1）新生科，2）分子诊断中心
  • 收稿日期:2017-07-12 修回日期:2017-08-18 出版日期:2017-08-25 发布日期:2017-08-25
  • 通讯作者: 杨琳

Pilot study of genetic etiology in neonates with agnogenic lethal fetal hydrops using whole-exome sequencing

YIN Rong 1）, YANG Lin 2）, HU Li-yuan 1）, ZHOU Wen-hao 2）   

  1. Children's Hospital of Fudan University, Shanghai 201102, China; 1) Department of Neonatology, 2) Molecular Diagnostic Centre
  • Received:2017-07-12 Revised:2017-08-18 Online:2017-08-25 Published:2017-08-25
  • Contact: YANG Lin

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摘要：

目的：针对不明原因致死性胎儿水肿的患儿行全外显子组测序，分析与胎儿水肿表型相关的潜在候选基因。方法：收集2011年1月1日至2017年6月1日复旦大学附属儿科医院（我院）收治的不明原因致死性胎儿水肿并行全外显子组检测的病例，采集与致死性胎儿水肿有关的母亲、围生期和新生儿因素，按照我院转化医学中心建立的高通量测序数据分析流程，采用ExAC数据库、千人基因组数据库和我院分子诊断中心已经进行建立的13 810例全外显子组数据，行后续数据分析。结果：符合本文纳入标准的不明原因致死性胎儿水肿患儿18例进入本文分析，男、女各9例，胎龄（34±2）周，体重（2 935±911）g。2例患儿母亲有因胎儿水肿或胸腔积液引产的不良孕产史，3例患儿为试管婴儿。常见的临床表型除胎儿水肿和羊水过多外，还包括心功能不全、休克和肺发育不全等。7例患儿检测到符合罕见潜在致病标准的变异共9个。5例患儿检测到的杂合变异，2个为有害变异（无义变异位于FOXF1基因，移码变异位于RASA1基因），3个错义变异（位于FOXC2基因）。2例患儿检测到的杂合变异，4个变异位于PIEZO1基因2个均为有害变异，位于DSP基因的2个变异均为错义变异。上述基因进行通路富集分析发现，多集中在心血管、血管和血管内皮生长因子等通路上。结论：在病因不明的致死性胎儿水肿病例中检测到罕见潜在致病变异，结合既往报道文献，FLT4、SPTB、PIEZO1和FOXC2基因可考虑作为胎儿水肿候选基因；首次提出FOXF1、RASA1和DSP基因可能与胎儿水肿表型相关。

Abstract:

Objective: To investigate potential candidate genes related to phenotype of agnogenic lethal hydrops using whole-exome sequencing.Methods: Data of neonates with agnogenic lethal hydrops were collected from Jan 1st 2011 to June 1st 2017 in Children's hospital of Fudan University (our hospital) and WES was employed to analyze their genotype. Maternal, perinatal and neonatal risk factors were also collected from each neonate. We used next-generation sequencing data analysis pipeline established by Translational Medical Center, Children's Hospital of Fudan University. Public databases were used including the exome aggregation consortium (ExAC), and the 1000 Genome Project, as well as in-house database including 13 810 WES data for variants annotation and filtering.Results: Eighteen neonates with agnogenic lethal hydrops were included in this study, and half of them were male. Their gestational ages were among 34±2 weeks and birth weight was around (2 935±911) g. There were 2 patients' mothers with history of induced abortion because of hydrops or thoracic effusion fetus and 3 patients were IVF (In-Vitro Fertilization) infants. Besides hydrops and polyhydramnios, the other common clinical phenotypes were cardiac dysfunction, shock and pulmonary dysplasia. Nine variants in 7 patients were identified fitting our criteria for rare and likely pathogenic, including 5 heterozygous variants in 5 genes and 4 compound heterozygous variants in 2 genes. Among the 5 heterozygous variants, 2 variants were deleterious (one nonsense in FOXF1 gene and one frameshift in RASA1 gene), 3 variants were missense in FOXC2, FLT4 and SPTB gene. Among the 4 compound heterozygous variants, both variants in PIEZO1 gene were deleterious (one splicing site and one frameshift), other two variants in DSP gene were missense. The pathway enrichment analysis showed that these genes identified in the 7 patients focused on blood vessel, cardiovascular system development and vascular endothelial growth factor receptor signaling pathway.Conclusion: Seven rare potential pathogenic gene variants were detected in agnogenic lethal hydrops neonates. Combined with previous literature, FLT4, SPTB, PIEZO1 and FOXC2 might be considered as candidate genes of fetal hydrops. Our study was the first report that suggested FOXF1, RASA1 and DSP genes could be related to the phenotype of fetal hydrops.