摘要
Abstract
ObjectiveTo investigate potential candidate genes related to phenotype of agnogenic lethal hydrops using whole-exome sequencing.MethodsData 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.ResultsEighteen 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.ConclusionSeven 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.关键词
胎儿水肿/致死性/全外显子技术Key words
Fetal hydrops/Lethal/Whole-exome sequencing
