Genetic Investigation of Minimally Verbal Children with ASD

项目概要/摘要 自闭症谱系障碍（ASD）在其临床表现上是高度异质性的，这使得自闭症患者的临床表现复杂化。 诊断、预后和治疗。随着对ASD遗传基础的了解越来越多，我们 挑战是了解遗传风险如何转化为特定的表型，轨迹和机制。的 对语言障碍（MV）儿童的深入表型分析和治疗提供了一个独特的机会， 确定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。此外，委员会认为， 将MV ASD队列加入到可用于分子研究的更广泛的自闭症家庭集合中， 增强我们对ASD遗传异质性的整体理解。该项目将 由加州大学洛杉矶分校的丹尼尔·格施温德博士和他的同事们进行。我们假设， MV儿童可能代表遗传上更同质的ASD群体，具有特征性遗传特征。 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（巴内特和货车Bon，2015; D 'Angelo等人，2016; DiStefano等人，2016; Niklasson等人，二○ ○九年; Penagarikano和Geschwind，2012年;货车Bon等人，2010年）。此外，罕见的、大效应量的新生突变 更有可能与更严重的表型相关，包括低智商和严重的语言 损伤（Geschwind和Konopka，2009;罗宾逊等人，2014; Sanders等人，2015年）。基因检测 使用微阵列和全外显子组测序（WES）在临床上用于评估ASD， 鉴定大效应致病拷贝数变体（CNV）和从头蛋白质破坏突变（Jeste 和Geschwind，2014;米勒等人，2010; Schaefer等人，2008年）。鉴于CNV的患病率是 与严重性相关，例如，那些低智商和语言障碍的人可能有CNV的频率， 高达25%（Jacquemont等人，2006年）和WES的产量可能是10- 20%，我们将使用SNP微阵列， 鉴定可能的致病CNV和WES，从而为一部分患者提供“分子诊断”。我们 将评估由于全基因组常见遗传变异导致的ASD易感性与 听觉和听觉功能的定量测量（项目1和2）;言语和语言能力 (Core B）;以及对干预措施的反应（项目3）。我们假设基因图谱可能与 对语言干预的反应（项目3），未来的目标是迈出第一步， 这些预测因素可能有助于前瞻性地将儿童置于最适当的干预措施中。

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.