自闭症谱系障碍儿童社会交往分型及启示

自闭症谱系障碍儿童的临床表现具有极大的异质性,因此,分型对ASD病因学研究、早期鉴别诊断以及康复训练具有重要作用。ASD儿童可分为3种社会交往类型:冷漠型、被动型、主动但怪异型。本文针对社会交往分型体系的提出、ASD儿童各社交类型的特点和ASD儿童社交分型问卷进行综述,以期为ASD病因学研究、三大理论的发展及康复训练计划的制定提供建议。     

基因拷贝数变异与智力障碍病因学研究进展

基因拷贝数变异(copy number variations,CNVs)是指DNA片段大小从1 kb至Mb的亚微观结构变异,已成为探讨与疾病相关遗传变异的研究热点,特别是神经认知系统的遗传病,如精神分裂症、智力障碍等综合征、本文综述了基因拷贝数变异与智力障碍的关联关系和基因拷贝数变异检测技术进展在智力障碍诊断中的应用,这对揭示智力障碍发病机制有着重要意义.     

基因拷贝数变异与智力障碍病因学研究进展

基因拷贝数变异(copy number variations,CNVs)是指DNA片段大小从1 kb至Mb的亚微观结构变异,已成为探讨与疾病相关遗传变异的研究热点,特别是神经认知系统的遗传病,如精神分裂症、智力障碍等综合征、本文综述了基因拷贝数变异与智力障碍的关联关系和基因拷贝数变异检测技术进展在智力障碍诊断中的应用,这对揭示智力障碍发病机制有着重要意义.     

基因拷贝数变异与智力障碍病因学研究进展

基因拷贝数变异(copy number variations,CNVs)是指DNA片段大小从1 kb至Mb的亚微观结构变异,已成为探讨与疾病相关遗传变异的研究热点,特别是神经认知系统的遗传病,如精神分裂症、智力障碍等综合征、本文综述了基因拷贝数变异与智力障碍的关联关系和基因拷贝数变异检测技术进展在智力障碍诊断中的应用,这对揭示智力障碍发病机制有着重要意义.     

自闭症谱系障碍儿童静息状态下脑电微状态研究

利用微状态分析方法,在静息状态下的脑电图(EEG)尺度上探究自闭症谱系障碍(ASD)儿童与正常儿童(TD)在脑机制上的差异.根据Cartool中的准则和不同微状态类别的数目对于被试者EEG数据的解释程度,确定微状态类别的数目为4;使用原子化与凝聚层次聚类算法,分割出个人水平和组水平上的微状态类别,分别标记为微状态A、B...     

拷贝数变异测序在智力障碍、发育迟缓及孤独谱系综合征的病因学分析中的应用

目的探讨拷贝数变异测序(CNV-seq)对于智力障碍(ID)、发育迟缓(DD)及孤独谱系障碍(ASD)患儿的诊断价值。方法收集2018年9月至2022年1月在深圳市南山区妇幼保健院诊断为ID、DD及ASD的患儿40例, 采集其外周血样, 分别进行染色体核型分析和CNV-seq检测, 查询ClinVar、DECIPHER、OMIM等数据库并结合生物信息学分析评估拷贝数变异(CNVs)的致病性。结果 40例患者检测出ID 16例(40.0%)、DD 15例(37.5%)、ASD 6例(15.0%)、ID合并DD为1例, ID合并ASD为2例。核型分析发现47, XY, +mar、46, XY, inv(8)(p11.2q21.2)、46, XX, del(5)(p14)以及46, XX[76]/46, X, dup(X)(p21.1q12)各1例, 染色体多态性2例。CNV-seq在20例患儿中共检出32处CNVs, 检出率(50.0%)明显高于核型分析。在10例(25.0%)患儿中发现了致病性CNVs(检出率为25.0%), 12例患者中发现了15处意义未明的CNVs(检出率为30.0%...     

用高分辨率微阵列比较基因组杂交分析一个孤独症家系的新生拷贝数变异

目的 对1个孤独症家系进行新发拷贝数变异(copy number variations,CNV)分析.方法 应用高分辨率全基因组芯片(Affymetrix Cytogenetics Whole-Genome 2.7M Array)检测该家系4名成员的基因组拷贝数,用Affymetrix Chromosome Analysis Suite软件分析结果.以基因组变异数据库亚洲正常人群及先证者父母、同胞为对照,分析先证者的新发CNV.结果 先证者存在89个新发拷贝数变异,其中5号、11号和14号染色体新发CNV总长占染色体全长超过1‰.3p26.1、4q22.2、5p15.2等区域也存在新发CNV,涉及GRM7、GRID2、CTNND2等10个与神经系统发育相关基因.结论 先证者多个与神经系统发育相关的基因存在新发拷贝数变异,这为探索孤独症的发病机理提供了新的线索.高分辨率基因组CNV芯片能够快速、准确地检测基因组的微小失衡,在遗传病诊断方面具有广阔的应用前景.     

自闭症谱系障碍的临床研究新进展(DSM-5新标准)

自闭症谱系障碍(ASD)是一组大脑发育障碍的复杂疾病。其特征是在不同程度上的社交互动障碍、语言和非语言的沟通有问题,以及重复的动作。美国精神病学会在2013年5月出版了《精神疾病诊断与统计手册》第5版(DSM-5)。在DSM-5诊断手册中,所有的自闭症障碍合并为一个诊断:自闭症谱系障碍(ASD)。在此之前,它们被认为是不同的亚型,包括自闭症、儿童期瓦解性障碍、阿斯伯格综合征、雷特氏症和待分类的广泛性发育障碍。自闭症的一些表现似乎呈现在非常早期的大脑发育时。然而,自闭症的最明显标志和自闭症的症状往往出现在2~3岁。近年来,对自闭症谱系障碍(ASD)的临床研究成为精神病学、心身医学和临床心理学的热点。根据DSM-5的标准和新的临床研究成果,本文对自闭症谱系障碍(ASD)的病因和发病机制、临床表现、诊断标准、心理评估、诊断和鉴别诊断、心理行为治疗、药物治疗和中医治疗进行了分析。     

一个孤独症谱系障碍核心家系 KIF1A基因错义变异及其蛋白表达和结构分析

目的:报告1个携带 KIF1A基因错义变异的孤独症谱系障碍核心家系,并分析 KIF1A基因的致病变异及其表达蛋白结构。 方法:提取患儿及其双亲外周血DNA,利用全外显子组测序(whole exome sequencing,WES)技术进行测序,并应用Sanger测序法进行验证。对可疑变...     

一个13q大片段缺失家系的产前诊断及遗传咨询

目的:对1个孕20 +周超声表现正常而无创产前检测提示为13q拷贝数异常的胎儿进行产前诊断。 方法:对胎儿羊水样本进行染色体核型分析和基因组拷贝数变异(copy number variation,CNV)检测;同时对胎儿父母行外周血染色体检查,以追溯胎儿染色体变异的来源。结果:基因组CNV检测提示...     

Recurrent copy number variations as risk factors for autism spectrum disorders: analysis of the clinical implications

Chromosomal microarray analysis (CMA) is currently considered a first‐tier diagnostic assay for the investigation of autism spectrum disorders (ASD), developmental delay and intellectual disability of unknown etiology. High‐resolution arrays were utilized for the identification of copy number variations (CNVs) in 195 ASD patients of Greek origin (126 males, 69 females). CMA resulted in the detection of 65 CNVs, excluding the known polymorphic copy number polymorphisms also found in the Database of Genomic Variants, for 51/195 patients (26.1%). Parental DNA testing in 20/51 patients revealed that 17 CNVs were de novo, 6 paternal and 3 of maternal origin. The majority of the 65 CNVs were deletions (66.1%), of which 5 on the X‐chromosome while the duplications, of which 7 on the X‐chromosome, were rarer (22/65, 33.8%). Fifty‐one CNVs from a total of 65, reported for our cohort of ASD patients, were of diagnostic significance and well described in the literature while 14 CNVs (8 losses, 6 gains) were characterized as variants of unknown significance and need further investigation. Among the 51 patients, 39 carried one CNV, 10 carried two CNVs and 2 carried three CNVs. The use of CMA, its clinical validity and utility was assessed.     

Prospective diagnostic analysis of copy number variants using SNP microarrays in individuals with autism spectrum disorders

Copy number variants (CNVs) have repeatedly been found to cause or predispose to autism spectrum disorders (ASDs). For diagnostic purposes, we screened 194 individuals with ASDs for CNVs using Illumina SNP arrays. In several probands, we also analyzed candidate genes located in inherited deletions to unmask autosomal recessive variants. Three CNVs, a de novo triplication of chromosome 15q11–q12 of paternal origin, a deletion on chromosome 9p24 and a de novo 3q29 deletion, were identified as the cause of the disorder in one individual each. An autosomal recessive cause was considered possible in two patients: a homozygous 1p31.1 deletion encompassing PTGER3 and a deletion of the entire DOCK10 gene associated with a rare hemizygous missense variant. We also identified multiple private or recurrent CNVs, the majority of which were inherited from asymptomatic parents. Although highly penetrant CNVs or variants inherited in an autosomal recessive manner were detected in rare cases, our results mainly support the hypothesis that most CNVs contribute to ASDs in association with other CNVs or point variants located elsewhere in the genome. Identification of these genetic interactions in individuals with ASDs constitutes a formidable challenge.     

ZDHHC15 as a candidate gene for autism spectrum disorder

The phenotypic repercussion of ZDHHC15 haploinsufficiency is not well-known. This gene was initially suggested as a candidate for X-linked mental retardation, but such an association was later questioned. We studied a multiplex family with three members with autism spectrum disorder (ASD) by array CGH, karyotype, exome sequencing and X-chromosome inactivation patterns. Medical history interviews, cognitive and physical examinations, and sensory profiling were also assessed. The three family members with ASD (with normal cognitive abilities and an abnormal sensory profile) were the only carriers of a 1.7 Mb deletion in the long arm of chromosome X, involving: ZDHHC15, MAGEE2, PBDC1, MAGEE1, MIR384 and MIR325. The normal chromosome X was preferentially inactivated in female carriers, and the whole exome sequencing of an affected family member did not reveal any additional genetic variant that could explain the phenotype. Thus, in the present family, ASD segregates with a deletion on chromosome X that includes ZDHHC15. Considering our results together with gene data (regarding function, expression, conservation and animal/cellular models), ZDHHC15 is a candidate gene for ASD. Emerging evidence also suggests that this gene could be associated with other neurodevelopmental disorders, with incomplete penetrance and variable expressivity.     

Segregating patterns of copy number variations in extended autism spectrum disorder (ASD) pedigrees

Autism spectrum disorder (ASD) is a relatively common childhood onset neurodevelopmental disorder with a complex genetic etiology. While progress has been made in identifying the de novo mutational landscape of ASD, the genetic factors that underpin the ASD's tendency to run in families are not well understood. In this study, nine extended pedigrees each with three or more individuals with ASD, and others with a lesser autism phenotype, were phenotyped and genotyped in an attempt to identify heritable copy number variants (CNVs). Although these families have previously generated linkage signals, no rare CNV segregated with these signals in any family. A small number of clinically relevant CNVs were identified. Only one CNV was identified that segregated with ASD phenotype; namely, a duplication overlapping DLGAP2 in three male offspring each with an ASD diagnosis. This gene encodes a synaptic scaffolding protein, part of a group of proteins known to be pathologically implicated in ASD. On the whole, however, the heritable nature of ASD in the families studied remains poorly understood.     

一例21号染色体三体嵌合型孤独症谱系障碍患儿的遗传学分析

目的对1例孤独症谱系障碍(autism spectrum disorder,ASD)伴有先天性心脏病的患儿进行细胞遗传学和分子遗传学分析,寻找其病因。方法取患儿及其父母的外周血进行常规染色体G显带核型分析,对患儿外周血提取的基因组DNA进行基于高通量测序的全外显子测序(whole exome sequencing,WES)和低覆盖度全基因组拷贝数变异测序(low-coverage massively parallel copy number variation sequencing,CNV-seq)检测分析,并利用染色体微阵列分析(chromosomal microarray analysis,CMA)进行验证。结果常规染色体G显带核型分析结果显示患儿及其父母染色体核型正常,患儿WES未检测到异常变异,而CNV-seq检测结果为47,XY,+21[10%]/46,XY[90%],提示存在低比例的21号染色体三体嵌合,CMA验证结果与CNV-seq结果一致。结论低比例的21号染色体三体嵌合除与唐氏综合征表型有关外,还可能与ASD的发生密切相关。基于高通量测序的WES及CNV-seq方法可为原因不明的ASD提供准确的遗传学诊断。     

Copy number changes of the microcephalin 1 gene (MCPH1) in patients with autism spectrum disorders

Autism spectrum disorder (ASD) represents a set of neurodevelopmental disorders with a strong genetic aetiology. Chromosomal rearrangements have been detected in 5–10% of the patients with ASD, and recent applications of array comparative genomic hybridisation (aCGH) are identifying further candidate regions and genes. In this study, we present four patients who implicate microcephalin 1 ( MCPH1) in band 8p23.1 as an ASD susceptibility gene. Patient 1 was a girl with a syndromic form of autistic disorder satisfying the Autism Diagnostic Interview-Revised (ADI-R), Autism Diagnostic Observation Schedule (ADOS) and Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria. Oligonucleotide aCGH (oaCGH) showed that she had a classic inv dup del(8)(qter-> p23.1::p23.1-> p21.2) containing at least three candidate genes; MCPH1 and DLGAP2 within the 6.9-Mb terminal deletion and NEF3 within the concomitant 14.1-Mb duplication. Three further patients with MCPH1 copy number changes were found using single-nucleotide polymorphism (SNP) array analysis in a cohort of 54 families with ASD patients. Our results show that ASD can be a component of the classical inv dup del(8) phenotype and identify changes in copy number of MCPH1 as a susceptibility factor for ASD in the distal short arm of chromosome 8.     

Copy number variation and association analysis of SHANK3 as a candidate gene for autism in the IMGSAC collection

SHANK3 is located on chromosome 22q13.3 and encodes a scaffold protein that is found in excitatory synapses opposite the pre-synaptic active zone. SHANK3 is a binding partner of neuroligins, some of whose genes contain mutations in a small subset of individuals with autism. In individuals with autism spectrum disorders (ASDs), several studies have found SHANK3 to be disrupted by deletions ranging from hundreds of kilobases to megabases, suggesting that 1% of individuals with ASDs may have these chromosomal aberrations. To further analyse the involvement of SHANK3 in ASD, we screened the International Molecular Genetic Study of Autism Consortium (IMGSAC) multiplex family sample, 330 families, for SNP association and copy number variants (CNVs) in SHANK3. A collection of 76 IMGSAC Italian probands from singleton families was also examined by multiplex ligation-dependent probe amplification for CNVs. No CNVs or SNP associations were found within the sample set, although sequencing of the gene was not performed. Our data suggest that SHANK3 deletions may be limited to lower functioning individuals with autism.