An X-linked long non-coding RNA, PTCHD1-AS, and the core features of autism.

There are around 100 genes or copy-number variations used in genetic testing for autism spectrum disorder (ASD)1,2. The established genes are protein coding, and the associated phenotypes usually extend beyond sociobehavioural traits seen in autism, including cognitive/medical complexities and attention deficit hyperactivity disorder (ADHD)3,4. We examined whole-genome sequencing data in cases of ASD (9,349) and controls (8,332) and identify 27 male individuals with ASD with X-chromosome microdeletions that implicate the long non-coding RNA PTCHD1-AS as an ASD-susceptibility gene (odds ratio = 2.56, P = 0.01). Two Ptchd1-as-knockout mouse models, which were created by disrupting/deleting the evolutionarily conserved exon 3, show ASD-like features in male mice, including increased repetitive behaviours and impaired social behaviour and communication without cognitive comorbidities or ADHD-like behaviours. Hippocampus-dependent synaptic function, complex learning and locomotor activity are unaffected in knockout mice. Native nuclear-enriched mouse Ptchd1-as showed sustained expression from postnatal day 7 onwards in the dorsal striatum, a predominantly GABAergic brain region that is implicated in ASD5. Multi-omics analysis revealed transcriptomic alterations in striatal oligodendrocytes, astrocytes and neurons impacting myelination and synaptic plasticity. Disrupting Ptchd1-as led to reductions in conventional protein kinase C (cPKC) isoforms, altered SRC and GSK-3α/β phosphorylation and enhanced striatal synaptic plasticity (long-term potentiation and long-term depression). Together, these findings implicate striatal molecular and circuit-level dysregulation through PTCHD1-AS in ASD aetiology.