TRRAP (transformation/transcription domain-associated protein) is a critical scaffold protein within histone acetyltransferase (HAT) complexes that orchestrates epigenetic transcription activation. As a component of the NuA4/TIP60 complex, TRRAP facilitates acetylation of nucleosomal histones H4 and H2A, enabling transcription activation 1. TRRAP serves as an adaptor linking transcription factors—including MYC, E2F1, E2F4, p53, and Sp1—to HAT complexes, thereby promoting their target gene expression 2. Additionally, TRRAP participates in the SWR1-like complex mediating histone H2A.Z removal from nucleosomes 3. In human neural stem cells, TRRAP cooperates with the chr7 remodeler CHD8 to regulate MYC and E2F target genes critical for cell-cycle progression 4. Pathogenic missense variants in TRRAP cause two distinct clinical spectra with strong genotype-phenotype correlation: a complex multi-systemic syndrome with brain, cardiac, and renal malformations, and autism spectrum disorder (ASD) with intellectual disability and epilepsy 5. TRRAP's intolerance to missense variation reflects its essential role in transcriptional regulation and cellular processes. Loss of TRRAP function leads to mislocalization of the NuA4/TIP60 complex and genome-wide redistribution of histone acetylation patterns 1, disrupting normal gene expression programs essential for neural development and function.