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

Early truncating KAT6A variants (exons 1-15) cause loss of function through nonsense-mediated decay, whereas late truncating variants (exons 16-17) escape it and produce gain of function.

Arboleda-Tham syndrome, caused by truncating KAT6A variants, is currently diagnosed as a single neurodevelopmental syndrome of variable severity. Using patient-derived iPSCs and multi-omics profiling, the authors show that this clinical stratification reflects two distinct molecular mechanisms determined by variant position: early truncating variants (exons 1-15) cause loss of function via nonsense-mediated decay, while late truncating variants (exons 16-17), which escape it, cause gain-of-function effects. These opposite mechanisms are mirrored by distinctive facial gestalt features and DNA-methylation episignatures, and invert the direction of change across neuronal gene regulation, metabolism and mitochondrial physiology. The distinction opens two divergent therapeutic routes: KAT6A inhibition for late truncating variants, loss-of-function rescue for early ones.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

If confirmed, this result makes the phrase "truncating KAT6A variant" insufficient in a report: exonic position becomes diagnostic-level information with opposite implications for therapeutic trials. The strongest argument for practice is the existence of distinct episignatures, since that is a laboratory-measurable marker, unlike facial gestalt whose inter-observer reproducibility remains to be established. Two caveats: this is a medRxiv preprint not yet peer reviewed, and the demonstration rests on iPSCs and omics data without prospective correlation to clinical course.

Analysis by Dr Thibaut Benquey