Characterization of De Novo Promoter Variants in Autism Spectrum Disorder with Massively Parallel Reporter Assays

Justin Koesterich, Joon Yong An, Fumitaka Inoue, Ajuni Sohota, Nadav Ahituv, Stephan J. Sanders, Anat Kreimer

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)


Autism spectrum disorder (ASD) is a common, complex, and highly heritable condition with contributions from both common and rare genetic variations. While disruptive, rare variants in protein-coding regions clearly contribute to symptoms, the role of rare non-coding remains unclear. Variants in these regions, including promoters, can alter downstream RNA and protein quantity; however, the functional impacts of specific variants observed in ASD cohorts remain largely uncharacterized. Here, we analyzed 3600 de novo mutations in promoter regions previously identified by whole-genome sequencing of autistic probands and neurotypical siblings to test the hypothesis that mutations in cases have a greater functional impact than those in controls. We leveraged massively parallel reporter assays (MPRAs) to detect transcriptional consequences of these variants in neural progenitor cells and identified 165 functionally high confidence de novo variants (HcDNVs). While these HcDNVs are enriched for markers of active transcription, disruption to transcription factor binding sites, and open chromatin, we did not identify differences in functional impact based on ASD diagnostic status.

Original languageEnglish
Article number3509
JournalInternational journal of molecular sciences
Issue number4
Publication statusPublished - 2023 Feb

Bibliographical note

Publisher Copyright:
© 2023 by the authors.


  • autism disease genetics
  • computational genomics
  • functional genomics
  • gene regulation
  • neural development

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry


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