PR domain-containing member 12 (PRDM12) is a key developmental transcription factor in sensory neuronal specification and survival. Patients with rare deleterious variants in PRDM12 are born with congenital insensitivity to pain (CIP) due to the complete absence of a subtype of peripheral neurons that detect pain. In this paper, we report two additional CIP cases with a novel homozygous PRDM12 variant. To elucidate the function of PRDM12 during mammalian development and adulthood, we generated temporal and spatial conditional mouse models. We find that PRDM12 is expressed throughout the adult nervous system. We observed that loss of PRDM12 during mid-sensory neurogenesis but not in the adult leads to reduced survival. Comparing cellular biophysical nociceptive properties in developmental and adult-onset PRDM12 deletion mouse models, we find that PRDM12 is necessary for proper nociceptive responses throughout life. However, we find that PRDM12 regulates distinct age-dependent transcriptional programs. Together, our results implicate PRDM12 as a viable therapeutic target for specific pain therapies even in adults.

Intellectual disabilities (ID) are a type of neurodevelopmental disorder (NDD). They can have a genetic cause, including an emerging class of ID centring around Rho GTPases, such as Ras-related C3 botulinum toxin substrate 1 (RAC1). Guidelines for establishing genetic causality include the use of cellular models, which often have morphological aberrations, a long-standing hallmark of ID. Disease cellular models can facilitate high-throughput screening (HTS) of chemical or genetic perturbations, which can provide translatable biological insight. Here, we discuss a class of IDs centring around RAC1. We review novel and established cellular models of ID, including mouse and human primary cells and reprogrammed or induced neurons. Finally, we review progress and remaining challenges in the adoption of HTS methodologies by the community studying neurological disorders. Rare Intellectual Disabilities: Insights into NeurodevelopmentCommon and rare (see Glossary) forms of ID are a type of NDD that have an estimated prevalence of 2-3% in the general population, with 0.3-0.5% classified as severe ID and 85% of cases classified as mild [1,2]. Genetic studies, including next-generation sequencing (NGS) technologies, have identified 2588 genes to be involved in ID thus far [3] and the exponential rate at which this number increases each year indicates that saturation in ID gene identification has not yet been reached [2]. Indeed, a recent study estimated that >1000 genes associated with developmental disorders have yet to be identified [4]. Characterising genetic contribution to observed neuropathological features of patients is not trivial. Field-accepted guidelines for assigning genetic disease-causality require bioinformatic, statistical, and experimental approaches, including the use of cellular and animal models of disease, which are particularly challenging for neuroscientists [5]. Nevertheless, due to technical advances, common molecular pathways in seemingly distinct IDs have been identified, including an emerging class of IDs centring around RAC1. Furthermore, established and novel cellular models of common and rare neurological disease have not only contributed to our understanding of genetic neuropathology, but also paved the way for scalable genetic and pharmacological screens. HighlightsNext-generation sequencing of patients with ID continues to identify genes important to neuronal development.