PERSPECTIVES Next-Generation Sequencing in Autism Spectrum Disorder

Autism spectrum disorder (ASD) is a common disorder that causes substantial distress. Heritability studies consistently show a strong genetic contribution, raising the hope that identifying ASD-associated genetic variants will offer insights into neurobiology and ultimately therapeutics. Next-generation sequencing (NGS) enabled the identification of disruptive variants throughout protein-coding regions of the genome. Alongside large cohorts and novel statistical methods, these NGS methods revolutionized ASD gene discovery. NGS methods have also contributed substantially to functional genetic data, such as gene expression, used to understand the neurobiological consequences of disrupting these ASD-associated genes. These functional data are also critical for annotating the noncoding genome as whole-genome sequencing (WGS) begins to provide initial insights outside of protein-coding regions. NGS methods still have a major role to play, as do similarly transformative advances in stem cell and gene-editing methods, in translating genetic discoveries into a first generation of ASD therapeutics.
Source: Cold Spring Harbor perspectives in medicine - Category: Research Authors: Tags: Next-Generation Sequencing in Medicine PERSPECTIVES Source Type: research

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ConclusionMEK-ERK and MNK-eIF4E pathways regulate protein translation, and our results suggest that aberrant translation distinct in TSC1/2-deficient NPCs could play a role in neurodevelopmental defects. Our data showing upregulation of these signaling pathways by rapamycin support a strategy to combine a MEK or a MNK inhibitor with rapamycin that may be superior for TSC-associated CNS defects. Importantly, our generation of isogenic sets of NPCs from TSC patients provides a valuable platform for translatome and large-scale drug screening studies. Overall, our studies further support the notion that early developmental eve...
Source: Molecular Autism - Category: Molecular Biology Source Type: research
AbstractMolybdenum cofactor sulfurase (MOCOS) gene encodes an enzyme which is involved in purine metabolism. Recent experiments have shown down-regulation of MOCOS in adult nasal olfactory stem cells of individuals with autism spectrum disorder (ASD). In the current study, we genotyped two single nucleotide polymorphisms (SNPs) within coding regions ofMOCOS gene (rs594445 and rs1057251) in 406 ASD patients and 411 age and sex-matched controls. The A allele of the rs594445 SNP was more prevalent among ASD cases compared with controls (OR (95% CI)  = 1.33 (1.07–1.64), adjustedP value  = 0.02...
Source: Metabolic Brain Disease - Category: Neurology Source Type: research
ConclusionsWe have provided evidence of morphological, physiological, and transcriptomic signatures of polygenic liability to ASD from an analysis of cellular models derived from a multiplex autism family. ASD is commonly inherited on the basis of additive genetic liability. Therefore, identifying convergent cellular and molecular phenotypes resulting from polygenic and monogenic susceptibility may provide a critical bridge for determining which of the disparate effects of rare highly deleterious mutations might also apply to common autistic syndromes.
Source: Molecular Autism - Category: Molecular Biology Source Type: research
ConclusionsThis is the first report to show that humanNRXN1 α+/ − neurons derived from ASD patients ’ iPSCs present novel phenotypes of upregulated VGCCs and increased Ca2+ transients, which may facilitate the development of drug screening assays for the treatment of ASD.
Source: Molecular Autism - Category: Molecular Biology Source Type: research
The syndromic autism spectrum disorder (ASD) Timothy Syndrome (TS) is caused by a point mutation in the alternatively spliced exon 8A of the calcium channel Cav1.2. Using mouse brain and human induced pluripotent stem cells (iPSCs), we provide evidence that the TS mutation prevents a normal developmental switch in Cav1.2 exon utilization, resulting in persistent expression of gain-of-function mutant channels during neuronal differentiation. In iPSC models, the TS mutation reduces the abundance of SATB2-expressing cortical projection neurons, leading to excess CTIP2+ neurons. We show that expression of TS-Cav1.2 channels in...
Source: eLife - Category: Biomedical Science Tags: Neuroscience Stem Cells and Regenerative Medicine Source Type: research
by Fanwei Zeng, Xuehai Ma, Lin Zhu, Qiang Xu, Yuzhe Zeng, Yue Gao, Guilin Li, Tiantian Guo, Haibin Zhang, Xiaoyan Tang, Ziqiang Wang, Zesen Ye, Liangkai Zheng, Hongfeng Zhang, Qiuyang Zheng, Kunping Li, Jinfang Lu, Xueting Qi, Hong Luo, Xian Zhang, Zhanxiang Wang, Yulin Zhou, Yi Yao, Rongqin Ke, Ying Zhou, Yan Liu, Hao Sun, Timothy Huang, Zhicheng Shao, Huaxi Xu, Xin Wang Ubiquitin-specific protease (USP) 6 is a hominoid deubiquitinating enzyme previously implicated in intellectual disability and autism spectrum disorder. Although these findings link USP6 to higher brain function, potential roles for USP6 in cognition hav...
Source: PLoS Biology: Archived Table of Contents - Category: Biology Authors: Source Type: research
This study shows that CA are released from periventricular and subpial regions to the cerebrospinal fluid and are present in the cervical lymph nodes, into which cerebrospinal fluid drains through the meningeal lymphatic system. We also show that CA can be phagocytosed by macrophages. We conclude that CA can act as containers that remove waste products from the brain and may be involved in a mechanism that cleans the brain. Moreover, we postulate that CA may contribute in some autoimmune brain diseases, exporting brain substances that interact with the immune system, and hypothesize that CA may contain brain markers that m...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
Authors: Gottlieb MM Abstract This paper develops mathematical models examining possible roles of oxytocin and oxytocin receptors in the development of autism. This is done by demonstrating that mathematical operations on normalized data from the Stanford study, which establishes a correspondence between severity of autism in children and their oxytocin blood levels, generate a graph that is the same as the graph of mathematical operations on a normalized theoretical model for the severity of autism. This procedure establishes the validity of the theoretical model and the significance of oxytocin receptors in autis...
Source: Computational and Mathematical Methods in Medicine - Category: Statistics Tags: Comput Math Methods Med Source Type: research
Autism spectrum disorders (ASDs) are developmental neuropsychiatric disorders with heterogeneous etiologies. As the incidence of these disorders is rising, such disorders represent a major human health problem with escalating social cost. Although recent years witnessed advances in our understanding of the genetic basis of some dysmorphic ASDs, little progress has been made in translating the improved understanding into effective strategies for ASD management or minimization of general ASD risk. Here we explore the idea, described in terms of the neural stem cell (NSC)/carnitine malnutrition hypothesis, that an unappreciat...
Source: Journal of Biological Chemistry - Category: Chemistry Authors: Tags: ASBMB Award Articles Source Type: research
Publication date: Available online 30 November 2019Source: Pharmacological ResearchAuthor(s): Francesca Pistollato, Tamara Yuliett Forbes-Hernández, Ruben Calderón Iglesias, Roberto Ruiz, Maria Elexpuru, Danila Cianciosi, Francesca Giampieri, Maurizio BattinoAbstractIn the last decade, the prevalence of autism spectrum disorders (ASD) has dramatically escalated worldwide. Currently available drugs mainly target some co-occurring symptoms of ASD, but are not effective on the core symptoms, namely impairments in communication and social interaction, and the presence of restricted and repetitive behaviors. On th...
Source: Pharmacological Research - Category: Drugs & Pharmacology Source Type: research
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