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

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.