Abstract
Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder, and the exact causal mechanism is unknown. Dysregulated allele-specific expression (ASE) has been identified in persons with ASD; however, a comprehensive analysis of ASE has not been conducted in a family quartet with ASD. To fill this gap, we analyzed ASE using genomic DNA from parent and offspring and RNA from offspring’s postmortem prefrontal cortex (PFC); one of the two offspring had been diagnosed with ASD. DNA- and RNA-sequencing revealed distinct ASE patterns from the PFC of both offspring. However, only the PFC of the offspring with ASD exhibited a mono-to-biallelic switch for LRP2BP and ZNF407. We also identified a novel site of RNA-editing in KMT2C in addition to new monoallelically-expressed genes and miRNAs. Our results demonstrate the prevalence of ASE in human PFC and ASE abnormalities in the PFC of a person with ASD. Taken together, these findings may provide mechanistic insights into the pathogenesis of ASD.
Highlights
Autism spectrum disorder (ASD) is a heritable neurodevelopmental disorder characterized by social difficulties, communication challenges, and repetitive behaviors[1]
We found a mono-to-biallelic switch for LRP2BP (LRP2 binding protein) and ZNF407 (Zinc finger protein 407) in the offspring diagnosed with ASD
When prefrontal cortex (PFC) miRNAs from the offspring with ASD were compared with those of the offspring without ASD, we found 105 up-regulated and 125 down-regulated miRNAs in the offspring diagnosed with ASD (Fig. 1e and Supplementary Table 7)
Summary
Autism spectrum disorder (ASD) is a heritable neurodevelopmental disorder characterized by social difficulties, communication challenges, and repetitive behaviors[1]. Medications can provide an improvement in behaviors for persons with ASD, they cannot reliably ameliorate all of the core symptoms of this disorder[3,4] This limitation of therapeutic efficacy is due to the heterogeneous and multifactorial causes of ASD, which include genetic components, environmental insults, and gene-environment interactions[5,6]. Altered gene expression in the brain has been consistently identified in persons with ASD through genome-wide analysis[7,8,9,10]. Despite the relevance of MAE to ASD, comprehensive analysis of MAE in a family quartet with ASD has not been conducted due to limited access to samples To address this critical knowledge gap, we investigated the role of ASE in the pathogenesis of ASD using special human parent-child quartet samples. Our results provide further evidence that ASE could contribute to ASD
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