{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T18:44:05Z","timestamp":1792521845513,"version":"4.5.0"},"reference-count":78,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"8","license":[{"start":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T00:00:00Z","timestamp":1787616000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2026,8,25]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>\n                      An estimated 1 in 500 people lives with hypertrophic cardiomyopathy (HCM), a disease for which genetic diagnosis can identify family members at risk and increasingly guide therapy. Variants in the\n                      <jats:italic toggle=\"yes\">MYBPC3<\/jats:italic>\n                      gene, which encodes cardiac myosin-binding protein C (cMyBP-C), account for a significant proportion of HCM cases. However, many of these are classified as variants of uncertain significance, complicating clinical decision-making. Scalable methods for variant interpretation in disease-specific cell types are crucial for understanding variant impact and uncovering disease mechanisms.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      We developed a scaled multidimensional mapping strategy to evaluate the functional impact of variants across a critical domain of cMyBP-C. We incorporate saturation base editing at the native\n                      <jats:italic toggle=\"yes\">MYBPC3<\/jats:italic>\n                      locus, a long-read RNA sequencing-enabled assay of variant splice effects, and measurements of HCM-relevant phenotypes, including cMyBP-C abundance, hypertrophic signaling, and ubiquitin-proteasome function in human induced pluripotent stem cell\u2013derived cardiomyocytes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      Our multidimensional mapping strategy enabled high-resolution functional analysis of\n                      <jats:italic toggle=\"yes\">MYBPC3<\/jats:italic>\n                      variants in induced pluripotent stem cell\u2013derived cardiomyocytes. Our massively parallel splicing assay identified novel splice-disrupting variants. Targeted transient base editing generated a comprehensive variant library at the native locus, capturing diverse variant effects on cellular HCM-relevant phenotypes. Integration of functional assays revealed that decreased cMyBP-C abundance is a key driver of HCM-related phenotypes. In parallel, downregulation of protein degradation was observed to correlate with\n                      <jats:italic toggle=\"yes\">MYBPC3<\/jats:italic>\n                      loss of function, and novel potential disease mechanisms were identified for missense variants near a critical binding domain. Bayesian estimates of variant effects enable the reclassification of clinical variants.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>This work provides a platform for extending genome engineering in induced pluripotent stem cells to multiplexed assays of variant effects across diverse disease-relevant cellular phenotypes, enhancing our understanding of variant pathogenicity and uncovering novel biological mechanisms that could inform therapeutic strategies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.125.075535","type":"journal-article","created":{"date-parts":[[2026,7,12]],"date-time":"2026-07-12T13:00:25Z","timestamp":1783861225000},"page":"733-749","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":2,"title":["Scaled Multidimensional Assays of Variant Effect Identify Sequence-Function Relationships in Hypertrophic Cardiomyopathy"],"prefix":"10.1161","volume":"154","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6129-9745","authenticated-orcid":true,"given":"Yuta","family":"Yamamoto","sequence":"first","affiliation":[{"name":"Stanford Center for Inherited Cardiovascular Disease, Department of Medicine, Division of Cardiovascular Medicine, (Y.Y., K.C., D.S., A.F., B.J.F., C.C., L.W., Q.W., J.E.G., Y.H., F.B., R.H.W., A.S., A.T., R.A., M.T.W., M.M., E.A.A., V.N.P.), Stanford School of Medicine, Palo Alto, CA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-1730-6149","authenticated-orcid":true,"given":"Kaiser","family":"Chua","sequence":"additional","affiliation":[{"name":"Stanford Center for Inherited Cardiovascular Disease, Department of Medicine, Division of Cardiovascular Medicine, (Y.Y., K.C., D.S., A.F., B.J.F., C.C., L.W., Q.W., J.E.G., Y.H., F.B., R.H.W., A.S., A.T., R.A., M.T.W., M.M., E.A.A., V.N.P.), Stanford School of Medicine, Palo Alto, CA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3399-9311","authenticated-orcid":true,"given":"David","family":"Staudt","sequence":"additional","affiliation":[{"name":"Stanford Center for Inherited Cardiovascular Disease, Department of Medicine, Division of Cardiovascular Medicine, (Y.Y., K.C., D.S., A.F., B.J.F., C.C., L.W., Q.W., J.E.G., Y.H., F.B., R.H.W., A.S., A.T., R.A., M.T.W., M.M., E.A.A., V.N.P.), Stanford School of Medicine, Palo Alto, CA."},{"name":"Department of Pediatrics (D.S., B.J.F.), Stanford School of Medicine, Palo Alto, CA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexis","family":"Ferrasse","sequence":"additional","affiliation":[{"name":"Stanford Center for Inherited Cardiovascular Disease, Department of Medicine, Division of Cardiovascular Medicine, (Y.Y., K.C., D.S., A.F., B.J.F., C.C., L.W., Q.W., J.E.G., Y.H., F.B., R.H.W., 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