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An X-linked long non-coding RNA, PTCHD1-AS, and the core features of autism
Clarrisa A Bradley1,2,3, Sangyoon Y Ko4,5,6,7, Meng Tian8
1The Centre for Applied Genomics, Program in Genetics & Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada. lisa.bradley@sickkids.ca.
Nature
|May 13, 2026
Summary
A new study identifies the long non-coding RNA PTCHD1-AS as a potential gene linked to autism spectrum disorder (ASD). Mouse models with disrupted PTCHD1-AS show ASD-like behaviors, suggesting its role in striatal circuit dysfunction.
Area of Science:
- Genetics
- Neuroscience
- Developmental Biology
Background:
- Genetic testing for autism spectrum disorder (ASD) currently relies on ~100 protein-coding genes or copy-number variations.
- Associated phenotypes often extend beyond sociobehavioral traits, including cognitive and medical complexities, and attention deficit hyperactivity disorder (ADHD).
Purpose of the Study:
- To investigate the role of the long non-coding RNA PTCHD1-AS in autism spectrum disorder (ASD) etiology.
- To explore the functional consequences of PTCHD1-AS disruption in mouse models.
Main Methods:
- Whole-genome sequencing analysis of 9,349 ASD cases and 8,332 controls.
- Creation and behavioral/molecular analysis of two Ptchd1-as-knockout mouse models.
- Multi-omics analysis of striatal tissue, including transcriptomics and protein signaling pathways.
Main Results:
- Identified X-chromosome microdeletions implicating PTCHD1-AS as an ASD-susceptibility gene (OR=2.56, P=0.01) in 27 male individuals with ASD.
- Ptchd1-as-knockout male mice exhibited increased repetitive behaviors and impaired social behavior/communication without cognitive or ADHD-like issues.
- Disruption of Ptchd1-as altered striatal molecular pathways, including cPKC isoforms, SRC and GSK-3α/β phosphorylation, and enhanced synaptic plasticity.
Conclusions:
- PTCHD1-AS is implicated as a novel ASD-susceptibility gene.
- Striatal molecular and circuit-level dysregulation due to PTCHD1-AS disruption contributes to ASD etiology.
- Ptchd1-as knockout mouse models provide a valuable tool for studying ASD-related neurobiology.
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