Each month Levy Library showcases the achievements of Mount Sinai faculty and researchers by highlighting an article and its altmetrics. Altmetrics are alternative measures of impact that capture non-traditional data like abstract views, article downloads, and social media activity. Our altmetrics data is provided by the PlumX platform.
This month we highlight: Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism. This article was written in part by Alexander Kolevzon MD; Behrang Mahjani PhD; Sven S. Sandin PhD; Avraham Reichenberg PhD; Danielle Halpern PsyD; Silvia De Rubeis PhD; and Michael S Breen PhD.
• 102 genes implicated in risk for autism spectrum disorder (ASD genes, FDR ≤ 0.1)
• Most are expressed and enriched early in excitatory and inhibitory neuronal lineages
• Most affect synapses or regulate other genes; how these roles dovetail is unknown
• Some ASD genes alter early development broadly, others appear more specific to ASD
We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n = 35,584 total samples, 11,986 with ASD). Using an enhanced analytical framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate of 0.1 or less. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained to have severe neurodevelopmental delay, whereas 53 show higher frequencies in individuals ascertained to have ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In cells from the human cortex, expression of risk genes is enriched in excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory-inhibitory imbalance underlying ASD.
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