PTCHD1 encodes a transmembrane protein that plays a crucial role in regulating synaptic function. PTCHD1 was first reported in relation to non-syndromic X-linked intellectual disability in 2015 (Chaudhry et al., PMID: 25131214). The clinical features of affected males include developmental delay, variable degrees of intellectual disability, and autism spectrum disorder or autistic features. Additionally, some patients may present hypotonia and subtle dysmorphic features. Females are usually unaffected.
Nine variants (frameshift and single gene deletions) that have been reported in nine probands in four publications (PMIDs: 25131214, 25356970, 26350204, 28934986) are included in this curation. Note that four large deletions involving only PTCHD1 (PMIDs: 25131214, 28934986) could not be formally entered as evidence due to technical limitations in the gene curation interface at the time of curation, but they each contribute 1.5 points. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by a mouse model (PMID: 27007844).
In summary, there is definitive evidence supporting the relationship between PTCHD1 and non-syndromic X-linked intellectual disability. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on August 15, 2018 (SOP Version 5).
Multiple independent reports of affected individuals with deleterious PTCHD1 variants, in addition to functional and mouse model evidence, support a compelling link between deleterious variants in PTCHD1 and X-linked intellectual disability.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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