Complete Disruption of Autism-Susceptibility Genes by Gene Editing Predominantly Reduces Functional Connectivity of Isogenic Human Neurons Journal Articles uri icon

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  • Autism spectrum disorder (ASD) is phenotypically and genetically heterogeneous. We present a CRISPR gene editing strategy to insert a protein tag and premature termination sites creating an induced pluripotent stem cell (iPSC) knockout resource for functional studies of ten ASD-relevant genes (AFF2/FMR2, ANOS1, ASTN2, ATRX, CACNA1C, CHD8, DLGAP2, KCNQ2, SCN2A, TENM1). Neurogenin 2 (NGN2)-directed induction of iPSCs allowed production of excitatory neurons, and mutant proteins were not detectable. RNA sequencing revealed convergence of several neuronal networks. Using both patch-clamp and multi-electrode array approaches, the electrophysiological deficits measured were distinct for different mutations. However, they culminated in a consistent reduction in synaptic activity, including reduced spontaneous excitatory postsynaptic current frequencies in AFF2/FMR2-, ASTN2-, ATRX-, KCNQ2-, and SCN2A-null neurons. Despite ASD susceptibility genes belonging to different gene ontologies, isogenic stem cell resources can reveal common functional phenotypes, such as reduced functional connectivity.


  • Deneault, Eric
  • White, Sean H
  • Rodrigues, Deivid C
  • Ross, P Joel
  • Faheem, Muhammad
  • Zaslavsky, Kirill
  • Wang, Zhuozhi
  • Alexandrova, Roumiana
  • Pellecchia, Giovanna
  • Wei, Wei
  • Piekna, Alina
  • Kaur, Gaganjot
  • Howe, Jennifer L
  • Kwan, Vickie
  • Thiruvahindrapuram, Bhooma
  • Walker, Susan
  • Lionel, Anath C
  • Pasceri, Peter
  • Merico, Daniele
  • Yuen, Ryan KC
  • Singh, Karun
  • Ellis, James
  • Scherer, Stephen W

publication date

  • November 2018