SPEN (spen family transcriptional repressor) is a nuclear transcriptional regulatory protein that functions as both a corepressor and transcriptional platform. SPEN acts as a negative regulator of the Notch signaling pathway by interacting with RBPSUH to prevent NOTCH1-mediated transactivation 1. The protein recruits histone deacetylase-containing complexes to mediate transcriptional repression and plays a critical role in X chromosome 1, where it nucleates supramolecular complexes (SMACs) containing multiple SPEN molecules that generate local protein gradients to propagate silencing across X-linked genes 2. SPEN interacts with the Xist lncRNA through its A-repeat domain and is essential for Xist-mediated gene silencing and chr1 modifications 3. SPEN haploinsufficiency causes a neurodevelopmental disorder with significant clinical overlap to proximal 1p36 deletion syndrome, presenting with developmental delay, intellectual disability, autism spectrum disorder, brain anomalies, congenital heart defects, and distinctive X chromosome 1 methylation episignatures in females 1. The gene's involvement in neurodevelopmental disorders is supported by large-scale sequencing studies identifying SPEN among genes enriched for de novo mutations in autism and other neurodevelopmental conditions 4. Additionally, SPEN mutations have been identified in prostate cancer genomics 5, suggesting broader roles in oncogenic pathways.