Computational Biology, Precision Health, Telethon Kids Institute, Perth Children’s Hospital, Nedlands, WA 6009, Australia; Translational Genetics, Precision Health, Telethon Kids Institute, Perth Children’s Hospital, Nedlands, WA 6009, Australia; Centre for Child Health Research, University of Western Australia, Nedlands, WA 6009, Australia; Corresponding author
Catherine A. Forbes
Translational Genetics, Precision Health, Telethon Kids Institute, Perth Children’s Hospital, Nedlands, WA 6009, Australia
Nicole C. Shaw
Translational Genetics, Precision Health, Telethon Kids Institute, Perth Children’s Hospital, Nedlands, WA 6009, Australia
Emma Kuzminski
Translational Genetics, Precision Health, Telethon Kids Institute, Perth Children’s Hospital, Nedlands, WA 6009, Australia; Centre for Child Health Research, University of Western Australia, Nedlands, WA 6009, Australia
Michelle Ward
Undiagnosed Diseases Program, Genetic Services of WA, Subiaco WA 6008, Australia
Gareth Baynam
Western Australian Register of Developmental Anomalies, King Edward Memorial Hospital, Subiaco, WA 6008, Australia; Undiagnosed Diseases Program, Genetic Services of WA, Subiaco WA 6008, Australia; Rare Care Centre, Perth Children’s Hospital, Nedlands, WA 6009, Australia
Timo Lassmann
Computational Biology, Precision Health, Telethon Kids Institute, Perth Children’s Hospital, Nedlands, WA 6009, Australia; Centre for Child Health Research, University of Western Australia, Nedlands, WA 6009, Australia
Vanessa S. Fear
Translational Genetics, Precision Health, Telethon Kids Institute, Perth Children’s Hospital, Nedlands, WA 6009, Australia; Centre for Child Health Research, University of Western Australia, Nedlands, WA 6009, Australia
Summary: 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 affected individuals 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 affected individual remains undiagnosed. A VUS (PTCHD1 c. 2489T>G) was identified in a child with autistic behavior, 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 modeling 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 and Genomics guidelines. In addition, our study provides molecular data on the role of PTCHD1 in the context of other neurodevelopmental disorders.
