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Typical for haploinsufficiency-associated genes, hundreds of unique loss-of-function pathogenic variants have been reported for\n                  <jats:italic>MYBPC3<\/jats:italic>\n                  \u2013 therapeutic gene editing to correct each of these variants poses major regulatory and logistical hurdles. Upregulating wild-type allele expression could offer a generalizable therapeutic strategy, but the capacity to modulate native\n                  <jats:italic>MYBPC3<\/jats:italic>\n                  transcription is unknown. Here, we present a variant-agnostic approach to rescue haploinsufficiency by mapping and rationally redesigning the\n                  <jats:italic>MYBPC3<\/jats:italic>\n                  promoter. Using massively parallel reporter assays (MPRAs) in human induced pluripotent stem cell-derived cardiomyocytes, we performed saturation mutagenesis of the\n                  <jats:italic>MYBPC3<\/jats:italic>\n                  promoter at single base-pair resolution. This defined a new class of clinically relevant noncoding loss-of-function variants while revealing essential cis-regulatory grammar anchored by key transcription factor binding sites (TFBSs). Furthermore, by systematically screening thousands of variant combinations, modular promoter elements, and heterologous TFBS insertions, we identified synergistic sequence edits that drive robust increases in\n                  <jats:italic>MYBPC3<\/jats:italic>\n                  expression. Together, our findings improve the clinical interpretation of noncoding variants and establish a scalable blueprint for promoter editing to treat\n                  <jats:italic>MYBPC3<\/jats:italic>\n                  -associated HCM and other haploinsufficient diseases.\n                <\/jats:p>","DOI":"10.64898\/2026.09.20.752987","type":"posted-content","created":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T02:35:11Z","timestamp":1790390111000},"source":"Crossref","is-referenced-by-count":0,"title":["Mapping and rewiring the\n                  <i>MYBPC3<\/i>\n                  promoter for rescue of haploinsufficiency driven hypertrophic cardiomyopathy"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8782-9342","authenticated-orcid":false,"given":"Aaron","family":"Renberg","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA"},{"name":"Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-5932-8628","authenticated-orcid":false,"given":"Savannah","family":"Coppersmith","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-7743-8943","authenticated-orcid":false,"given":"Owen","family":"Merritt","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0373-1290","authenticated-orcid":false,"given":"Yao-Chang","family":"Tsan","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esraa","family":"Ismail","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7062-060X","authenticated-orcid":false,"given":"Jennasea","family":"Licata","sequence":"additional","affiliation":[{"name":"Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, 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