Synaptic Dysfunction in Human Neurons With Autism-Associated Deletions in PTCHD1-AS

P. Joel Ross, Wen Bo Zhang, Rebecca S.F. Mok, Kirill Zaslavsky, Eric Deneault, Lia D'Abate, Deivid C. Rodrigues, Ryan K.C. Yuen, Muhammad Faheem, Marat Mufteev, Alina Piekna, Wei Wei, Peter Pasceri, Rebecca J. Landa, Andras Nagy, Balazs Varga, Michael W. Salter, Stephen W. Scherer, James Ellis

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


Background: The Xp22.11 locus that encompasses PTCHD1, DDX53, and the long noncoding RNA PTCHD1-AS is frequently disrupted in male subjects with autism spectrum disorder (ASD), but the functional consequences of these genetic risk factors for ASD are unknown. Methods: To evaluate the functional consequences of PTCHD1 locus deletions, we generated induced pluripotent stem cells (iPSCs) from unaffected control subjects and 3 subjects with ASD with microdeletions affecting PTCHD1-AS/PTCHD1, PTCHD1-AS/DDX53, or PTCHD1-AS alone. Function of iPSC-derived cortical neurons was assessed using molecular approaches and electrophysiology. We also compiled novel and known genetic variants of the PTCHD1 locus to explore the roles of PTCHD1 and PTCHD1-AS in genetic risk for ASD and other neurodevelopmental disorders. Finally, genome editing was used to explore the functional consequences of deleting a single conserved exon of PTCHD1-AS. Results: iPSC-derived neurons from subjects with ASD exhibited reduced miniature excitatory postsynaptic current frequency and N-methyl-D-aspartate receptor hypofunction. We found that 35 ASD-associated deletions mapping to the PTCHD1 locus disrupted exons of PTCHD1-AS. We also found a novel ASD-associated deletion of PTCHD1-AS exon 3 and showed that exon 3 loss altered PTCHD1-AS splicing without affecting expression of the neighboring PTCHD1 coding gene. Finally, targeted disruption of PTCHD1-AS exon 3 recapitulated diminished miniature excitatory postsynaptic current frequency, supporting a role for the long noncoding RNA in the etiology of ASD. Conclusions: Our genetic findings provide strong evidence that PTCHD1-AS deletions are risk factors for ASD, and human iPSC-derived neurons implicate these deletions in the neurophysiology of excitatory synapses and in ASD-associated synaptic impairment.

Original languageEnglish (US)
Pages (from-to)139-149
Number of pages11
JournalBiological psychiatry
Issue number2
StatePublished - Jan 15 2020


  • Autism spectrum disorder
  • Excitatory synapses
  • Genetics
  • Induced pluripotent stem cells
  • Long noncoding RNA
  • Neurons

ASJC Scopus subject areas

  • Biological Psychiatry


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