Genetic Investigation of Minimally Verbal Children with ASD

患有自闭症谱系障碍（ASD）的最少语言儿童的基因调查

基本信息

批准号：
10689725
负责人：
DANIEL H GESCHWIND
金额：
$ 44.88万
依托单位：
BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10689725
关键词：
Age Area Articulation Asthma Attention deficit hyperactivity disorder Auditory Behavioral Behavioral Symptoms Biocompatible Materials Biological Characteristics Child Childhood Chromosome abnormality Clinical Code Cognitive Collection Copy Number Polymorphism DNA Data Diabetes Mellitus Diagnosis Doctor of Philosophy Early Diagnosis Early Intervention Etiology Evaluation Family Family member Foundations Frequencies Future Genes Genetic Genetic Diseases Genetic Heterogeneity Genetic Risk Genetic Variation Goals Heterogeneity Inherited Intellectual functioning disability Intervention Investigation Karyotype determination procedure Language Language Delays Language Disorders Measures Mediating Molecular Molecular Analysis Molecular Diagnosis Motor Mutation Neurobehavioral Manifestations Neurodevelopmental Disorder Neurophysiology - biologic function Outcome Parents Pathogenicity Patients Phenotype Play Population Prevalence Prognosis Proteins Resolution Risk Marker Role SNP genotyping Saliva Severities Siblings Single Nucleotide Polymorphism Speech Speech Development Subgroup Susceptibility Gene Symptoms Syndrome Testing Translating Treatment outcome Variant Work autism spectrum disorder autistic children cohort de novo mutation exome sequencing genetic analysis genetic architecture genetic risk factor genetic testing genome-wide insertion/deletion mutation language impairment language outcome minimally verbal neurophysiology neuropsychiatry oral motor patient subsets polygenic risk score proband prospective response risk variant social transmission process treatment response verbal

项目摘要

PROJECT SUMMARY/ ABSTRACT Autism Spectrum Disorder (ASD) is highly heterogeneous in its clinical presentation, which complicates diagnosis, prognosis and treatment. As the genetic basis for ASD becomes increasingly understood, we are challenged to understand how genetic risk translates to specific phenotypes, trajectories and mechanisms. The deep phenotyping and treatment of children who are minimally verbal (MV) provides a unique opportunity to identify potential genetic risk factors or predictors, which is the major aim of this genetics project. Moreover, the addition of the MV ASD cohort to the broader collection of autism families available for molecular study will enhance our understanding of the genetic heterogeneity underlying ASD as a whole. This project will be undertaken by Daniel Geschwind, MD, PhD, and his colleagues at UCLA. We hypothesize that subgroups of MV children may represent genetically more-homogeneous cohorts of ASD with characteristic genetic profiles. Specific syndromes associated with ASD have specific behavioral and cognitive profiles, including language phenotypes (Barnett and van Bon, 2015; D'Angelo et al., 2016; DiStefano et al., 2016; Niklasson et al., 2009; Penagarikano and Geschwind, 2012; van Bon et al., 2010). Further, rare, large effect size de novo mutations are more likely to be associated with more severe phenotypes, including low IQ and severe language impairment (Geschwind and Konopka, 2009; Robinson et al., 2014; Sanders et al., 2015). Genetic testing using microarrays and whole-exome sequencing (WES) is clinically indicated in the evaluation of ASD to identify large effect pathogenic copy number variants (CNV) and de novo protein disrupting mutations (Jeste and Geschwind, 2014; Miller et al., 2010; Schaefer et al., 2008). Given that the prevalence of CNV is associated with severity, e.g., those with low IQ and language impairment may have a frequency of CNV as high as 25% (Jacquemont et al., 2006) and the yield of WES is likely 10-20%, we will use SNP microarrays to identify likely causal CNVs and WES, thereby providing a “molecular diagnosis” for a subset of patients. We will evaluate the correlation between ASD liability due to common genetic variation genome-wide and quantitative measures of oromotor and auditory functioning (Projects 1 and 2); speech and language ability (Core B); and response to intervention (Project 3). We hypothesize that genetic profile may correlate with response to language intervention (Project 3), with the future goal of taking a first step toward generating predictors that may be useful to prospectively place children into the most appropriate interventions.

项目概要/摘要自闭症谱系障碍 (ASD) 的临床表现具有高度异质性，这使随着自闭症谱系障碍（ASD）的遗传基础越来越被人们所了解，我们对自闭症谱系障碍（ASD）的诊断、预后和治疗有了越来越多的了解。面临的挑战是了解遗传风险如何转化为特定的表型、轨迹和机制。对语言能力极低的儿童进行深入表型分析和治疗提供了一个独特的机会识别潜在的遗传风险因素或预测因子，这是该遗传学项目的主要目标。将 MV ASD 队列添加到可用于分子研究的更广泛的自闭症家庭集合中将增强我们对整个自闭症谱系障碍的遗传异质性的理解。由加州大学洛杉矶分校的 Daniel Geschwind 博士和他的同事承担。 MV 儿童可能代表具有特征性遗传特征的遗传上更加同质的 ASD 群体。与 ASD 相关的特定综合征具有特定的行为和认知特征，包括语言表型（Barnett 和 van Bon，2015；D'Angelo 等，2016；DiStefano 等，2016；Niklasson 等，2009； Penagarikano 和 Geschwind，2012；van Bon 等人，2010）。更有可能与更严重的表型相关，包括低智商和严重的语言（Geschwind 和 Konopka，2009；Robinson 等，2014；Sanders 等，2015）。使用微阵列和全外显子组测序（WES）在临床上可用于评估自闭症谱系障碍（ASD）识别大效应致病性拷贝数变异 (CNV) 和从头蛋白质破坏突变 (Jeste 和 Geschwind，2014；Miller 等，2010；Schaefer 等，2008）。与严重程度相关，例如，智商低且语言障碍的人的 CNV 频率可能为高达 25% (Jacquemont et al., 2006)，而 WES 的产量可能为 10-20%，我们将使用 SNP 微阵列来识别可能的因果 CNV 和 WES，从而为一部分患者提供“分子诊断”。将评估由于全基因组范围内的常见遗传变异引起的自闭症谱系障碍（ASD）责任与口部运动和听觉功能的定量测量（项目 1 和 2）；（核心 B）；以及对干预的反应（项目 3）。对语言干预的反应（项目 3），未来的目标是迈出第一步预测因素可能有助于前瞻性地将儿童置于最合适的干预措施中。