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However, network perturbations in CHD remain poorly understood. We report an integrated functional-epigenomics approach to CHD, focusing on the cardiac homeodomain (HD) transcription factor NKX2-5, mutations which cause diverse heart structural and conduction defects. We selected twelve NKX2-5 CHD variants affecting different residue classes - homeodomain DNA base-contacting, backbone-contacting and helix-stabilizing, and those affecting other conserved protein:protein interaction (PPI) domains. In HL-1 cardiomyocytes, we profiled genome-wide DNA targets of NKX2-5 wild type (WT) and variants, their DNA binding affinity and specificity, PPI with known NKX2-5 cofactors and chromatin search dynamics. Variants showed diverse yet class-specific behaviours. All variants failed to bind many WT targets but retained binding to a subset of core cardiomyocyte-related targets, and bound hundreds of unique \u201coff-targets\u201d via changes to DNA binding site specificity, homodimerization, cofactor interactions and chromatin search functions. Our data suggest that complex residue-by-residue scale epigenomic, biochemical and chromatin search defects involving both loss-and gain-of-function contribute to CHD. These findings may inform precision molecular therapeutic approaches in patients with CHD.<\/jats:p>","DOI":"10.1101\/2025.06.20.659510","type":"posted-content","created":{"date-parts":[[2025,6,20]],"date-time":"2025-06-20T22:00:16Z","timestamp":1750456816000},"source":"Crossref","is-referenced-by-count":0,"title":["NKX2-5 congenital heart disease mutations show diverse loss and gain of epigenomic, biochemical and chromatin search functions underpinning pathogenicity"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5852-6705","authenticated-orcid":false,"given":"Alexander O.","family":"Ward","sequence":"first","affiliation":[{"name":"Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst, Sydney, New South Wales, Australia"},{"name":"School of Clinical Medicine, UNSW Sydney, Kensington, New South Wales, 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