Disruption at the PTCHD1 Locus on Xp22.11 in Autism Spectrum Disorder and Intellectual Disability

Autism is a common neurodevelopmental disorder with a complex mode of inheritance. It is one of the most highly heritable of the complex disorders, however, the underlying genetic factors remain largely unknown. Here, we report mutations in the X-chromosome PTCHD1 (patched-related) gene, in seven families with autism spectrum disorder (ASD) and in three families with intellectual disability (ID). A 167 Kb microdeletion spanning exon 1 was found in two brothers, one with ASD the other with learning disability and ASD features, and a 90 Kb microdeletion spanning the entire gene was found in three males with ID in a second family. In 900 ASD and 208 ID male probands we identified seven different missense changes in eight probands, all male and inherited from unaffected mothers, and not found in controls. Two of the ASD individuals with missense changes also carried a de novo deletion at another ASD-susceptibility locus (DPYD and DPP6), suggesting complex genetic contributions. In additional males with ASD, we identified deletions in the 5’ flanking region of PTCHD1 disrupting a complex non-coding RNA and potential regulatory elements; equivalent changes were not found in male control individuals (p=1.2 ×10-5). Systematic screening at PTCHD1 and 5’-flanking regions, suggests involvement of this locus in ~1% of ASD and ID individuals.