Gene of the Month - May: PTCHD1-AS
Microdeletions affecting the X‑chromosomal lncRNA locus PTCHD1-AS increase the risk of autism and are particularly associated with the core features of autism spectrum disorder (ASD), namely altered social interaction and communication as well as repetitive behaviours. In a Nature study, the authors analyzed whole‑genome sequencing data from 9,349 individuals with ASD and 8,332 controls and identified 27 boys with X‑chromosomal microdeletions involving PTCHD1-AS.
PTCHD1-AS encodes a long non-coding RNA (lncRNA). These RNA molecules span more than 200 nucleotides and are not translated into a protein but instead modulate the expression of other genes and can, for example, influence chromatin structure and transcription or act as scaffolds and guides for protein and RNA complexes, including in the nervous system. The Xp22.11 locus harboring PTCHD1-AS had already been linked to ASD in previous copy-number variation studies; the new data now point more specifically to PTCHD1-AS itself as a key risk locus within this region.
Using genomic analyses, human neural stem cell experiments and mouse models, the study demonstrates that disruption of PTCHD1-AS is sufficient to drive ASD-related biology. The findings indicate that PTCHD1-AS perturbation primarily affects the striatum, a brain region involved in the control of behaviour, where it alters gene regulation, myelination and synaptic plasticity. Moreover, PTCHD1-AS was shown to regulate expression of the neighbouring gene DDX53, whereas the protein-coding gene PTCHD1 remained largely unaffected. The study results thus support the view that, in addition to protein-coding genes, regulatory RNA loci such as PTCHD1-AS can make a direct contribution to ASD pathogenesis.
Bradley CA, Ko SY, Tian M, …, Scherer SW. An X-linked long non-coding RNA, PTCHD1-AS, and the core features of autism. Nature. 2026 May 13. doi: 10.1038/s41586-026-10515-6. Epub ahead of print.