SET Domain Genes in Neurodevelopmental Disorders

Neurodevelopmental disorders (NDDs) comprise a genetically and clinically heterogeneous group of conditions, with disruption of chromatin regulation and developmental gene-expression programs representing an important molecular mechanism underlying their pathogenesis. SET domain-containing (SETD) proteins constitute a diverse family of chromatin regulators that primarily mediate histone methylation, although some lack demonstrated intrinsic catalytic activity or modify non-histone substrates. Pathogenic variants in multiple SETD genes, including SETD1A, KMT2D, SETD2, NSD1, and EZH2, cause NDDs characterized by developmental delay, intellectual disability, speech and language impairment, autism-related features, epilepsy, growth abnormalities, and congenital anomalies. Representative examples include SETD1A-related neurodevelopmental disorder (OMIM #619056), KMT2D-related Kabuki syndrome type 1 (OMIM #147920), SETD2-related Luscan-Lumish syndrome (OMIM #616831), NSD1-related Sotos syndrome (OMIM #117550), and EZH2-related Weaver syndrome (OMIM #277590). In this review, we summarize the classification, domain architecture, and molecular functions of human SETD proteins and integrate clinical findings with mechanistic insights obtained from genetically modified mouse models. These studies reveal substantial cross-species convergence in cognitive, behavioral, synaptic, and developmental phenotypes while also demonstrating that individual SETD proteins regulate distinct molecular processes. Importantly, phenotypic similarity does not necessarily indicate a common molecular mechanism, and variant-specific effects, including loss-of-function, gain-of-function, dominant-negative, and substrate-selective alterations, must be considered when interpreting experimental models. Several studies further demonstrate partial reversibility of molecular and behavioral abnormalities through restoration of SETD protein function, inhibition of opposing chromatin-modifying enzymes such as LSD1, or correction of downstream signaling pathways. These findings suggest that therapeutic opportunities may extend beyond transcriptional regulation to downstream processes including translation, synaptic function, and cellular signaling. Integrating human genetics with animal and human cellular models will therefore be essential for defining shared and gene-specific mechanisms and identifying therapeutically actionable pathways in SETD-related NDDs.