Dominant truncating variants in KAT6A cause two neurodevelopmental disorders with opposite gene regulatory and metabolic changes

O_FIG O_LINKSMALLFIG WIDTH=191 HEIGHT=200 SRC="FIGDIR/small/26358095v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@ebc2a2org.highwire.dtl.DTLVardef@374956org.highwire.dtl.DTLVardef@1afebc9org.highwire.dtl.DTLVardef@a0fbd6_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGRAPHICAL ABSTRACTC_FLOATNO C_FIG KEY POINTSO_LITruncating variant location within KAT6A determines outcome: nonsense-mediated decay either silences early-truncating variants or spares late-truncating variants, producing loss- or gain-of-function and two distinct neurodevelopmental disorders. C_LIO_LIEarly- and late-truncating KAT6A variants affect gene regulation in opposite directions centered on a KAT6A-FOS-RBFOX-PTBP axis, stalling development at distinct stages. C_LIO_LIEarly- and late-truncating KAT6A variants drive inverse metabolic states in neurons via a multi-tiered mechanism, unveiling KAT6As complex role in human metabolism. C_LIO_LIPairing clinical patient assessment with multi-omic profiling of patient-derived stem cells is a powerful strategy for cracking pathogenic mechanisms in rare Mendelian disease. C_LIO_LIChemical inhibitors targeting epigenes can be used as disease-modifying strategies for Chromatinopathies, but only if their underlying pathogenic mechanism is known. C_LI Arboleda-Tham Syndrome (ARTHS), caused by truncating variants in KAT6A, is currently diagnosed as a single neurodevelopmental syndrome with variable severity of intellectual disability and multi-system findings. Here, we reveal that this clinical stratification reflects fundamentally distinct molecular mechanisms driven by variant position in the gene. Using patient-derived iPSCs and multi-omics profiling, we demonstrate that early-truncating variants (exons 1-15) cause loss-of-function via nonsense-mediated decay (NMD), while late-truncating variants (exons 16-17) that escape NMD cause gain-of-function effects. These opposite mechanisms are reflected in distinctive facial gestalt features and DNA-methylation episignatures and invert the direction of change across neuronal gene regulation, metabolism, and mitochondrial physiology. This mechanistic distinction enables precision therapeutics: late-truncating variants are amenable to KAT6A inhibition, while early-truncating variants require loss-of-function rescue. Variant-level stratification is therefore essential: mechanistic understanding--not gene-level diagnosis alone--is prerequisite for developing rational therapeutic strategies in rare Mendelian disease.