Neurite outgrowth deficits caused by rare PLXNB1 mutation in pediatric bipolar disorder

: Pediatric Bipolar Disorder (PBD) is a severe mood dysregulation condition 1% of children and teens in the United States. It is associated with recurrent episodes of psychosis and depression and an increased risk of suicidality. However, the genetics and neuropathology of PBD are largely unknown. Here, we used a combinatorial family-based approach to characterize the cellular, molecular, genetic, and network-level deficits associated with PBD. We recruited a PBD patient and three unaffected family members from a family with a history of psychiatric illnesses. Using resting-state functional magnetic resonance imaging (rs-fMRI), we detected altered resting state functional connectivity in the patient as compared to the unaffected sibling. Using transcriptomic profiling of patient and control induced pluripotent stem cell (iPSC) derived telencephalic organoids, we found aberrant signaling in the molecular pathways related to neurite outgrowth. We corroborated the presence of neurite outgrowth deficits in patient iPSC-derived cortical neurons and identified a rare homozygous loss-of-function PLXNB1 variant (c.1360C>C; p.Ser454Arg) in the patient. Expression of wildtype but not PLXNB1 variant rescued neurite outgrowth deficit in patient neurons. These results suggest that functional PLXNB1 is an important regulator of neurite development in cortical neurons and that dysregulation of PLXNB1-mediated signaling cascades may contribute to an increased risk of PBD and other mood dysregulation-related disorders by disrupting neurite outgrowth and brain connectivity. Overall, the study demonstrates how a family-based combinatorial approach can be used to identify and study rare variants in psychiatric disorders to gain novel insights into molecular and cellular abnormalities. Psychiatric illnesses touch the lives of all beings. Yet, our understanding of the fundamental biological mechanisms of these illnesses is limited. An important question is how genetic polymorphisms in psychiatric disorders link up with abnormalities at the cellular and neural circuitry level, in individual patients. We propose a novel approach that is capable of identifying genetic, cellular, and neural circuit-level deficits in patients with psychiatric illnesses. We applied this approach and uncovered a homozygous PLXNB1 variant that causes neurite outgrowth deficits in a patient with pediatric bipolar disorder. We also identified functional connectivity differences in this patient compared to the unaffected sibling. This combinatorial approach could advance our understanding of the genetic and biological mechanisms in psychiatric disorders. cell-type-specific markers compared to unaffected organoids. Together, these results indicate that patient and control organoids model similar early developmental stages and consist of similar types of cells, but may have deficits related to neurite development, axon guidance, or synapse assembly. 8pcw to 1 year. Spearman’s correlation