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    Single-cell transcriptome identifes molecular subtype of autism spectrum disorder impacted by de novo loss-of-function variants regulating glial cells

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    204-2021.45 Nasna Nassir.pdf (3.627Mb)
    Date
    2021
    Author
    Nassir, Nasna
    Bankapur, Asma
    Ali, Abdulrahman
    Ahmed, Awab
    Inuwa, Ibrahim M.
    Shabestari, Seyed Ali Safzadeh
    AlBanna, Ammar
    Berdiev, Bakhrom K.
    Uddin, Mohammed
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    Abstract
    Background: In recent years, several hundred autism spectrum disorder (ASD) implicated genes have been discov ered impacting a wide range of molecular pathways. However, the molecular underpinning of ASD, particularly from the point of view of ‘brain to behaviour’ pathogenic mechanisms, remains largely unknown. Methods: We undertook a study to investigate patterns of spatiotemporal and cell type expression of ASD-impli cated genes by integrating large-scale brain single-cell transcriptomes (>million cells) and de novo loss-of-function (LOF) ASD variants (impacting 852 genes from 40,122 cases). Results: We identifed multiple single-cell clusters from three distinct developmental human brain regions (ante rior cingulate cortex, middle temporal gyrus and primary visual cortex) that evidenced high evolutionary constraint through enrichment for brain critical exons and high pLI genes. These clusters also showed signifcant enrichment with ASD loss-of-function variant genes (p<5.23 × 10–11) that are transcriptionally highly active in prenatal brain regions (visual cortex and dorsolateral prefrontal cortex). Mapping ASD de novo LOF variant genes into large-scale human and mouse brain single-cell transcriptome analysis demonstrate enrichment of such genes into neuronal sub types and are also enriched for subtype of non-neuronal glial cell types (astrocyte, p<6.40× 10–11, oligodendrocyte, p<1.31× 10–09). Conclusion: Among the ASD genes enriched with pathogenic de novo LOF variants (i.e. KANK1, PLXNB1), a subgroup has restricted transcriptional regulation in non-neuronal cell types that are evolutionarily conserved. This association strongly suggests the involvement of subtype of non-neuronal glial cells in the pathogenesis of ASD and the need to explore other biological pathways for this disorder.
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    https://repository.mbru.ac.ae/handle/1/778
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