An estimated 3.5-5.9% of the global population live with rare diseases, and approximately 80% of these diseases have a genetic cause. Rare genetic diseases are difficult to diagnose, with some patients experiencing diagnostic delays of 5-30 years. Next generation sequencing has improved clinical diagnostic rates to 33-48%. In a majority of cases, novel variants potentially causing the disease are discovered. These variants require functional validation in specialist laboratories, resulting in a diagnostic delay. In the interim, the finding is classified as a genetic variant of uncertain significance (VUS) and the patient remains undiagnosed. A VUS (PTCHD1 c. 2489T>G) was identified in a child with autistic behaviour, global developmental delay and hypotonia. Loss of function mutations in PTCHD1 are associated with autism spectrum disorder and intellectual disability; however, the molecular function of PTCHD1, and its role in neurodevelopmental disease is unknown. Here, we apply CRISPR gene editing and induced pluripotent stem cell (iPSC) neural disease modelling to assess the variant. During differentiation from iPSCs to neural progenitors, we detect subtle, but significant gene signatures in synaptic transmission and muscle contraction pathways. Our work supports the causal link between the genetic variant and the child’s phenotype, providing evidence for the variant to be considered a pathogenic variant according to the American College of Medical Genetics guidelines. Additionally, our study provides molecular data on the role of PTCHD1 in the context of other neurodevelopmental disorders.
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