Allele-specific expression in a family quartet with autism reveals mono-to-biallelic switch and novel transcriptional processes of autism susceptibility genes

Sci Rep. 2018 Mar 9;8(1):4277. doi: 10.1038/s41598-018-22753-4.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Alleles*
  • Autism Spectrum Disorder / genetics*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Female
  • Humans
  • Low Density Lipoprotein Receptor-Related Protein-2
  • Male
  • MicroRNAs / genetics
  • Pedigree
  • Prefrontal Cortex / metabolism
  • RNA Editing*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • DNA-Binding Proteins
  • KMT2C protein, human
  • LRP2BP protein, human
  • Low Density Lipoprotein Receptor-Related Protein-2
  • MicroRNAs
  • Transcription Factors
  • ZNF407 protein, human