Investigating the role of the PTCHD1-PTCHD1-AS risk locus in Autism Spectrum Disorder

Autism Spectrum Disorder (ASD) is a prevalent neurodevelopmental disorder. Individuals with ASD exhibit social communication deficits, sensory differences and display restrictive, repetitive behaviors. Our genomic studies strongly implicate that the PTCHD1 / PTCHD1-AS locus on chromosome X is a penetrant susceptibility locus in males, contributing to autism spectrum disorder and intellectual disability in ~ 1% of cases. Genes at this locus include protein-coding genes PTCHD1, DDX53 and the long non-coding RNA PTCHD1-AS (head-to-head configuration). Characterisation of ASD deletion variants in murine Ptchd1-as (Ptchd1-as Ex3-/y and Ptchd1-as PolyA/y ) exhibit ASD associated social behavioural deficits, altered transcriptomics (examined with bulkRNAseq, single nuq-Seq, droplet digital PCR) and proteomic expression profiles at the synapse and nucleus. Higher order learning and the synaptic correlates of learning (LTP / LTD) in the hippocampus appear normal suggesting PTCHD1-AS loss of function (LOF) variants faithfully recapitulate a specific ASD phenotype. When investigating a potential regulatory relationship between the two genes, we find that Ptchd1-as ASD associated deletions have a modest effect on Ptchd1 expression. Instead a LOF variant within Ptchd1 (Ptchd1 Ex2-/y) induces a strong up regulation of multiple isoforms of Ptchd1-as, which suggests a protective effect against the development of ASD.