Studies of genomic copy number variants (CNVs) have identified genes associated with autism spectrum disorder (ASD) and intellectual disability (ID) such as NRXN1, SHANK2, SHANK3 and PTCHD1. Deletions have been reported in PTCHD1 however there has been little information available regarding the clinical presentation of these individuals. Herein we present 23 individuals with PTCHD1 deletions or truncating mutations with detailed phenotypic descriptions. The results suggest that individuals with disruption of the PTCHD1 coding region may have subtle dysmorphic features including a long face, prominent forehead, puffy eyelids and a thin upper lip. They do not have a consistent pattern of associated congenital anomalies or growth abnormalities. They have mild to moderate global developmental delay, variable degrees of ID, and many have prominent behavioral issues. Over 40% of subjects have ASD or ASD-like behaviors. The only consistent neurological findings in our cohort are orofacial hypotonia and mild motor incoordination. Our findings suggest that hemizygous PTCHD1 loss of function causes an X-linked neurodevelopmental disorder with a strong propensity to autistic behaviors. Detailed neuropsychological studies are required to better define the cognitive and behavioral phenotype.

Genome-wide single nucleotide polymorphism (SNP) data from 936 bipolar disorder (BD) individuals and 940 psychiatrically healthy comparison individuals of North European descent were analyzed for copy number variation (CNV). Using multiple CNV calling algorithms, and validating using in vitro molecular analyses, we identified CNVs implicating several candidate genes that encode synaptic proteins, such as DLG1, DLG2, DPP6, NRXN1, NRXN2, NRXN3, SHANK2, and EPHA5, as well as the neuronal splicing regulator RBFOX1 (A2BP1), and neuronal cell adhesion molecule CHL1. We have also identified recurrent CNVs on 15q13.3 and 16p11.2-regions previously reported as risk loci for neuropsychiatric disorders. In addition, we performed CNV analysis of individuals from 215 BD trios and identified de novo CNVs involving the NRXN1 and DRD5 genes. Our study provides further evidence of the occasional involvement of genomic mutations in the etiology of BD, however, there is no evidence of an increased burden of CNVs in BD. Further, the identification of CNVs at multiple members of the neurexin gene family in BD individuals, supports the role of synaptic disruption in the etiology of BD.

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BackgroundGenomic copy number variants (CNVs) have identified genes associated with autism spectrum disorder (ASD) and intellectual disability (ID). Recently, we reported on 23 individuals in 17 families with loss CNVs or frame-shifting indels disrupting PTCHD1. However, little is known for the function of PTCHD1.Objectives PTCHD1, an X-linked gene for ASD and/or (ID), encodes a protein with homology to the sonic hedgehog (Shh) receptors PTCH1 and 2, and has been reported to show similar Gli repression activity. However, little else is known about the function of PTCHD1 or the pathway (s) that are perturbed by PTCHD1 mutations leading to ASD/ID.Design/methodWe looked at the effect of over-expression of PTCHD1 on transcription levels of neuronal and synapse-related genes. We also included a truncated construct lacking the C-terminal four amino acids, Ile-Thr-Thr-Val (ITTV) of PTCHD1, which is predicted to interact with the PDZ domains of proteins. We tested the transcription of Shh and its putative receptor, Ptchd1, and Smoothened (Smo), from mouse embryonic and postnatal brains. We also analysed the expression of PTCHD1 and Smo in primary cilia.ResultsTranscriptional analysis showed Shh, Ptch1, and Smo expressed in developing mouse embryonic and postnatal hippocampus, but with gradually decreasing levels, whereas Ptchd1 levels steadily increase, suggesting that Ptchd1 may be more relevant in later embryonic and postnatal neurodevelopment. Preliminary results indicate that PTCHD1 is able to localise to the cilia.A significant increase in level of transcription of NLGN1 and CNTNAP1 that is dependent on the C-terminal four amino acids of PTCHD1 suggests either a regulatory or a downstream effect of PTCHD1 on these genes via a PDZ-domain containing protein. Positive PTCHD1 immunolabeling was visible in the hippocampal neurons. Preliminary results also suggest localization of PTCHD1 in cilia.ConclusionsWe report here a potential role for the PDZ binding domain in PTCHD1 in regulating expression of Nlgn1 and Cntnap1. PDZ domains are found in many eukaryotic and bacterial proteins, and in particular many proteins that are important for synaptic functioning.We speculate that PTCHD1 localization to primary cilia in hippocampal neurons could inhibit the Hh pathway by excluding SMO, allowing cilia to function as Shh sensors, in a manner similar to that of PTCH1, during neurodevelopment.The PTCHD1 gene has a role in a neurobiological pathway that delivers information to cells during brain development and CNVs and mutations may disrupt crucial developmental processes, contributing to the onset of autism.