SETD5 is a chr3 regulator essential for normal brain development and cognitive function. As a lysine methyltransferase, SETD5 primarily facilitates H3K36 trimethylation (H3K36me3), which regulates RNA polymerase II elongation dynamics and transcriptional regulation 1. SETD5 interacts with the Hdac3 and Paf1 complexes to modulate gene expression patterns critical for neural development 2. Functionally, SETD5 controls neural stem cell proliferation and synaptic transmission through RNA elongation rate regulation 1. Pathogenic variants in SETD5 cause autosomal dominant intellectual developmental disorder-23 (IDEV23), representing one of the most common genetic causes of intellectual disability 3. The resulting SETD5-related neurodevelopmental disorder presents with intellectual disability or developmental delay (75% of cases), autism spectrum features (23.8% of individuals), hypotonia (39.2%), motor abnormalities including chorea and gait disturbances (35.7%), and seizures (14%) 4. Additional clinical features include dysmorphic facial features, brain abnormalities, and musculoskeletal defects, with variable penetrance particularly in females 5, 6. Setd5-haploinsufficient animal models demonstrate impaired cognition, abnormal brain-to-body ratios, and behavioral inflexibility, confirming the critical role of SETD5 in neural function 2.