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：
10470956
负责人：
DANIEL H GESCHWIND
金额：
$ 44.83万
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/10470956
关键词：
Age Area 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 Lead Measures Mediating Microscopic 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 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 disorder control exome sequencing genetic analysis genetic architecture genetic risk factor genetic testing genome-wide insertion/deletion mutation language impairment language outcome neurophysiology neuropsychiatry oral motor patient subsets polygenic risk score proband prospective response risk variant social treatment response

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.

项目摘要/摘要自闭症谱系障碍（ASD）在其临床表现中高度异质，这使复杂诊断，预后和治疗。随着ASD的遗传基础变得越来越了解，我们是挑战要了解遗传风险如何转化为特定表型，轨迹和机制。这对最小口头（MV）的儿童的深层表型和治疗提供了独特的机会确定潜在的遗传危险因素或预测因素，这是该遗传学项目的主要目的。而且，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中增强我们对整个ASD潜在的遗传异质性的理解。这个项目将是由医学博士Daniel Geschwind和他在UCLA的同事承担。我们假设 MV儿童可能代表具有特征性遗传特征的ASD的基因统一同胞。与ASD相关的特定综合症具有特定的行为和认知概况，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年； Van Bon等，2010）。此外，罕见的，大小的从头突变更可能与更严重的表型相关，包括低智商和严重的语言损害（Geschwind和Konopka，2009； Robinson等，2014； Sanders等，2015）。基因检测在评估ASD至确定大型效应致病拷贝数变体（CNV）和从头蛋白质破坏突变（小丑和Geschwind，2014年； Miller等人，2010年； Schaefer等，2008）。鉴于CNV的患病率是与严重程度相关，例如，智商低和语言障碍的人可能具有CNV的频率高达25％（Jacquemont等，2006），WES的产量可能为10-20％，我们将使用SNP微阵列进行确定可能的因果CNV和WES，从而为一部分患者提供“分子诊断”。我们将评估由于普通遗传变异全基因组和 OroMotor和听觉功能的定量度量（项目1和2）；言语和语言能力（核心B）;和对干预的反应（项目3）。我们假设遗传特征可能与对语言干预的反应（项目3），未来的目标是迈出第一步预测因素可能对前瞻性将儿童置于最适当的干预措施中很有用。