{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T12:29:28Z","timestamp":1786710568064,"version":"build-2736575974"},"posted":{"date-parts":[[2026,8,14]]},"group-title":"Genetic and Genomic Medicine","reference-count":0,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"National Institute of Neurological Disorders and Stroke","award":["F31NS141668"],"award-info":[{"award-number":["F31NS141668"]}]},{"name":"Eli and Edythe Broad Stem Cell Training Fellowship"},{"award":["Junior Faculty Award"],"award-info":[{"award-number":["Junior Faculty Award"]}],"id":[{"id":"https:\/\/ror.org\/000dswa46","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/01nebar93","id-type":"ROR","asserted-by":"publisher"}]},{"name":"California Institute for Regenerative Medicine","award":["DISC0-14519"],"award-info":[{"award-number":["DISC0-14519"]}]},{"name":"KAT6 Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,8,14]]},"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.64898\/2026.08.11.26358095","type":"posted-content","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T11:30:18Z","timestamp":1786707018000},"source":"Crossref","is-referenced-by-count":0,"title":["Dominant truncating variants in KAT6A cause two neurodevelopmental disorders with opposite gene regulatory and metabolic changes."],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2053-6713","authenticated-orcid":false,"suffix":"BS","given":"Aileen A.","family":"Nava","sequence":"first","affiliation":[{"name":"1) Genetics & Genomics Home Area, Human Genetics Ph.D program, Graduate Programs in Bioscience, UCLA, Los Angeles, CA, USA.\n2) Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, 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