Relevance to Autism

Analysis of induced pluripotent stem cells (iPSCs) from subjects with ASD with deletions affecting PTCHD1-AS (previously reported in Noor et al., 2010 and Chaudhry et al., 2015) demonstrated that iPSC-derived neurons exhibited reduced miniature excitatory postsynaptic current (mESPC) frequency and N-methyl-D-asparate receptor hypofunction (Ross et al., 2019). A novel deletion encompassing the third exon of PTCHD1-AS was observed in three brothers with ASD in the same report; impaired synaptic function was subsequently observed both in CRISPR-edited neurons with a targeted deletion of PTCHD1-AS exon 3 and in iPSC-derived neurons from one of the three ASD-affected brothers. An X-chromosome-wide association study of 6,873 individuals with autism from MSSNG, SSC, and SPARK (5,639 males and 1,234 females) and 8,981 controls (3,911 males and 5,070 females) in Mendes et al., 2025 identified an intronic SNP in PTCHD1-AS that reached the significance threshold for association in meta-XWAS and both-XWAS analyses; furthemore, rare CNV deletions (<1% frequency in gnomAD) overlapping at least one exon of PTCHD1-AS were found to be enriched in male ASD cases from MSSNG, SSC, and SPARK compared to unaffected family members in this report. Bradley et al., 2026 examined whole-genome sequencing data in ASD cases (9,349) and controls (8,332) and identified 27 male individuals with ASD with microdeletions within PTCHD1-AS exons that were associated with an increased risk of ASD (odds ratio 2.56, P=0.01); in the same report, the authors found that two mouse models disrupting the canonical exon 3 of Ptchd1-as showed ASD-like features in male mice, including increased repetitive behaviors and impaired social interaction and communication without cognitive comorbidities or ADHD-like behaviors.

Molecular Function

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References