Genetic background of idiopathic neurodevelopmental delay patients with significant brain deviation volume  

作　　者：Xiang Chen Yuxi Chen Kai Yan Huiyao Chen Qian Qin Lin Yang Bo Liu Guoqiang Cheng Yun Cao Bingbing Wu Xinran Dong Zhongwei Qiao Wenhao Zhou 

机构地区：[1]Department of Neonatology,Children’s Hospital of Fudan University,National Children’s Medical Center,Shanghai 201102,China [2]Institutes of Biomedical Sciences,Fudan University,Shanghai 200032,China [3]Shanghai Key Laboratory of Birth Defects,The Translational Medicine Center of Children Development and Disease of Fudan University,Children’s Hospital of Fudan University,National Children’s Medical Center,Shanghai 201102,China [4]Department of Pediatric Endocrinology and Inherited Metabolic Diseases,Children’s Hospital of Fudan University,National Children’s Medical Center,Shanghai 201102,China [5]Department of Radiology,Children’s Hospital of Fudan University,National Children’s Medical Center,Shanghai 201102,China [6]State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science,Institutes of Brain Science,Fudan University,Shanghai 200433,China

出　　处：《Chinese Medical Journal》2023年第7期807-814,共8页中华医学杂志（英文版）

基　　金：grants from the Science and Technology Commission of Shanghai Municipal(No.19411964400);Shanghai Municipal Science and Technology Major Project(No.2018SHZDZX01);ZJLab.

摘　　要：Background:Significant brain volume deviation is an essential phenotype in children with neurodevelopmental delay(NDD),but its genetic basis has not been fully characterized.This study attempted to analyze the genetic factors associated with significant whole-brain deviation volume(WBDV).Methods:We established a reference curve based on 4222 subjects ranging in age from the first postnatal day to 18 years.We recruited only NDD patients without acquired etiologies or positive genetic results.Cranial magnetic resonance imaging(MRI)and clinical exome sequencing(2742 genes)data were acquired.A genetic burden test was performed,and the results were compared between patients with and without significant WBDV.Literature review analyses and BrainSpan analysis based on the human brain developmental transcriptome were performed to detect the potential role of genetic risk factors in human brain development.Results:We recruited a total of 253 NDD patients.Among them,26 had significantly decreased WBDV(<-2 standard deviations[SDs]),and 14 had significantly increased WBDV(>+2 SDs).NDD patients with significant WBDV had higher rates of motor development delay(49.8%[106/213]vs.75.0%[30/40],P=0.003)than patients without significant WBDV.Genetic burden analyses found 30 genes with an increased allele frequency of rare variants in patients with significant WBDV.Analyses of the literature further demonstrated that these genes were not randomly identified:burden genes were more related to the brain development than background genes(P=1.656e^(-9)).In seven human brain regions related to motor development,we observed burden genes had higher expression before 37-week gestational age than postnatal stages.Functional analyses found that burden genes were enriched in embryonic brain development,with positive regulation of synaptic growth at the neuromuscular junction,positive regulation of deoxyribonucleic acid templated transcription,and response to hormone,and these genes were shown to be expressed in neural progenitors.Based on single

关 键 词：Brain volume Burden genes CRANIAL EXOME Transcriptome Gestational age Gene frequency PHENOTYPE Magnetic resonance imaging Neuromuscular junction INTERNEURONS 

分 类 号：R741[医药卫生—神经病学与精神病学]