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

发布时间：2018-04-17 03:32

  本文选题：胎儿水肿 + 致死性　； 参考：《中国循证儿科杂志》2017年04期

【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Ex AC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 analyze the potential candidate genes associated with fetal edema phenotype in children with unexplained fatal fetal edema.Methods from January 1, 2011 to June 1, 2017, the patients with unexplained fatal fetal edema and total exon group were collected from pediatric hospital affiliated to Fudan University (our hospital), and mothers associated with fatal fetal edema were collected.Perinatal and neonatal factors, according to the high-throughput sequencing data analysis process established by the Center for Transforming Medicine in our hospital, Ex AC database was used.The data of 13 810 cases of total exon set from the human genome database and the molecular diagnosis center of our hospital were analyzed.Results 18 children with unexplained fatal fetal edema, 9 male and 9 female, were included in the analysis. The gestational age was 34 卤2 weeks.A total of 2 935 卤911)g.2 cases of fetal edema or pleural effusion were found to have a history of poor pregnancy and labor. 3 cases were in vitro.In addition to fetal edema and amniotic fluid, common clinical phenotypes include cardiac dysfunction,Heterozygosity was detected in 9 out of 7 children with shock and pulmonary dysplasia, and 2 were deleterious (nonsense mutation located in FOXF1 gene).Frameshift mutation was located in RASA1 gene, and 3 missense mutations (located in heterozygosity of FOXC2 gene were detected in 2 cases of children with FOXC2 gene). The 4 mutations located in PIEZO1 gene were both deleterious and the 2 mutations in DSP gene were missense mutations.The results of pathway enrichment analysis showed that these genes were mainly concentrated in cardiovascular, vascular and vascular endothelial growth factor pathways.Conclusion A rare and potential mutation was detected in fatal fetal edema with unknown etiology. Combined with the previous literature, the gene of PIEZO1 and FOXC2 may be considered as candidate genes for fetal edema.It is suggested for the first time that FOXF1 RASA1 and DSP genes may be associated with fetal edema phenotype.
【作者单位】： 复旦大学附属儿科医院新生科;复旦大学附属儿科医院分子诊断中心;
【分类号】：R714.5
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本文编号：1761899