Rare inherited missense variants of POGZ associate with autism risk and disrupt neuronal development

This 2019 study identified rare inherited POGZ variants in families with autism spectrum disorder (ASD) and investigated their functional impact. Findings: In a large autism cohort, the authors found an enrichment of inherited missense POGZ variants in affected individuals compared to controls. Two specific missense changes were characterized in vitro: both POGZ variants impaired neuronal differentiation when introduced into human neural progenitor cells, leading to altered expression of synaptic genes and disrupted neuronal morphology. These cellular phenotypes mirror those seen with POGZ loss-of-function, suggesting the missense changes are deleterious. The study concludes that not only de novo truncating mutations but also rare inherited missense POGZ variants can contribute to autism risk by perturbing neurodevelopment.