Table 5. Epigenetic mechanisms implicated in NDDs.

Mechanism	Example	Effect on gene expression	Associated NDD	Environmental sensitivity
DNA methylation	Rare epivariations at dosage-sensitive genes	Silencing or activation	ASD, Schizophrenia	Folate, toxins, maternal stress
Histone propionylation	BRPF1-KAT6 complex dysfunction	Reduced H3K23 propionylation	Syndromic ID	Propionate, HDAC inhibitors
Histone acetylation	EP400 mutations (chromatin remodeler)	Dysregulation of epilepsy/NDD genes	Epilepsy, ID	Metabolic intermediates, neuronal activity
Noncoding RNA (snRNA)	RNU4-2 mutations (minor spliceosome)	Global splicing defect of U12-type introns	Syndromic ID, hypotonia, seizures	None reported
Long noncoding RNA	Brain-enriched lncRNAs in ASD CNVs	Altered transcriptional regulation	ASD	Unknown
Genomic imprinting	15q11.2 maternal vs. paternal inheritance	Parental-origin-specific monoallelic expression	Angelman, Prader-Willi	Maternal intrauterine environment

This table summarizes major epigenetic mechanisms involved in the pathogenesis of NDDs. For each mechanism, a representative example is provided along with its molecular effect on gene expression, the associated NDD phenotype, and known or suspected environmental sensitivity. DNA methylation epivariations are rare locus-specific changes that can mimic sequence mutations. Histone modifications include propionylation (BRPF1-KAT6) and acetylation (EP400). Noncoding RNA mechanisms encompass the minor spliceosomal RNA RNU4-2 (mutations cause syndromic intellectual disability) and long noncoding RNAs enriched in ASD-associated CNVs. Genomic imprinting refers to parent-of-origin dependent gene expression, classically illustrated by 15q11.2 in Angelman and Prader-Willi syndromes. ASD, autism spectrum disorder; CNV, copy number variant; HDAC, histone deacetylase; ID, intellectual disability; NDD, neurodevelopmental disorder.