DE NOVO VARIANTS IN THE POLY(RC)-BINDING PROTEIN GENE <i>PCBP1</i> CAUSE A NEURODEVELOPMENTAL DISORDER

Poly(rC)-binding protein 1 (PCBP1), a splicing factor and key member of the hnRNP E family, was initially characterized for its tumor suppressive properties. More recently, its role in regulating gene expression in the brain and nervous system has attracted growing interest. Through an international multicenter collaboration, we identified 13 <i>de novo</i> pathogenic variants in <i>PCBP1</i> across 13 unrelated families. All affected individuals exhibited intellectual disability (ID), with autism spectrum disorder (ASD) as a prominent feature. Functional analysis in primary hippocampal mouse neuron cultures demonstrated that <i>PCBP1</i> variants impair dendritic arborization, underscoring their deleterious effects. Transcriptomic profiling by RNA sequencing of subjects-derived T cells showed a distinctive signature characterized by significantly increased exon skipping. These results highlight the essential role of PCBP1 in neurogenesis and neuritogenesis, revealing the impact of loss-of-function variants in cells harboring <i>PCBP1</i> pathogenic variants, thereby confirming the link between splicing defects and neurodevelopmental disorders. Collectively, our findings demonstrate the critical role of <i>PCBP1</i> in neurodevelopment, reaffirming the importance of splicing regulation in mammalian neurodevelopment.