ArticleCirculation2026
Scaled Multidimensional Assays of Variant Effect Identify Sequence-Function Relationships in Hypertrophic Cardiomyopathy.
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Article in Circulation, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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3citing papers in PubMed
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Who cites it
3 citing papers in PubMed.
- Cardiomyocyte vulnerability to lamin polymer disruption revealed by saturation mutagenesis.bioRxiv : the preprint server for biology · 2026Article
- High-Throughput Methods for Variant Functional Assessment in Cardiac Disease.Circulation. Genomic and precision medicine · 2026Review
- Editing stem cell genomes at scale to measure variant effects in diverse cell and genetic contexts.medRxiv : the preprint server for health sciences · 2025Article
Corrections and comments
- Update of
Authors and funding
27 authors.
Yuta YamamotoStanford 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.ORCID 0000-0001-6129-9745
Kaiser ChuaStanford 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.ORCID 0009-0009-1730-6149
David StaudtStanford 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.ORCID 0000-0002-3399-9311
Alexis FerrasseStanford 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.
Anna KirillovaMedical Scientist Training Program, University of Pittsburgh, PA (A.K.).ORCID 0000-0003-2113-5257
Hannah N De JongDepartment of Genetics, Stanford School of Medicine, Palo Alto, CA. (H.N.D.J., J.E.G.).ORCID 0000-0002-8699-9702
Brendan J FloydStanford 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.ORCID 0000-0003-3185-0174
Christian CadischStanford 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.ORCID 0009-0008-4822-312X
Laurens WielStanford 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.ORCID 0000-0003-3410-760X
Qianru WangStanford 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.ORCID 0000-0002-7219-7522
Matthew J O'NeillBrigham and Women's Hospital, HMS, Boston, MA (M.J.O., C.A.M.).
Daniel TabetDonnelly Centre and Department of Molecular Genetics, University of Toronto, ON, Canada (D.T., F.P.R.).ORCID 0009-0006-5480-7733
John E GoryznskiStanford 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.
Yong HuangStanford 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.ORCID 0009-0000-6727-4960
Fang BaiStanford 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.ORCID 0000-0003-0639-8104
Rachel H WilsonStanford 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.ORCID 0000-0003-3114-7040
Arman SharmaStanford 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.
Althea TapalesStanford 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.
Rani AgrawalStanford 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.
Matthew T WheelerStanford 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.ORCID 0000-0001-8721-3022
Mark MercolaStanford 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.ORCID 0000-0002-1430-2013
Calum A MacRaeBrigham and Women's Hospital, HMS, Boston, MA (M.J.O., C.A.M.).ORCID 0000-0001-5181-2664
Dan M RodenDepartment of Medicine, Division of Genomic Medicine and Clinical Pharmacology (D.M.R., A.M.G.), Vanderbilt University Medical Center, Nashville, TN.ORCID 0000-0002-6302-0389
Frederick P RothDonnelly Centre and Department of Molecular Genetics, University of Toronto, ON, Canada (D.T., F.P.R.).ORCID 0000-0002-6628-649X
Andrew M GlazerDepartment of Medicine, Division of Genomic Medicine and Clinical Pharmacology (D.M.R., A.M.G.), Vanderbilt University Medical Center, Nashville, TN.ORCID 0000-0002-3938-4713
Euan A Ashley *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.ORCID 0000-0001-9418-9577
Victoria N Parikh *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.ORCID 0000-0002-5138-5559
Funding
Stanford Mendelian Genomics Research CenterU01HG011762 · NHGRI · STANFORD UNIVERSITY · PI Jonathan Adam Bernstein, Stephen Montgomery · 2021 to 2026
$16.7MSystematically mapping variant effects for cardiovascular genesR01HL164675 · NHLBI · VANDERBILT UNIVERSITY MEDICAL CENTER · PI ASHLEY, EUAN A, RODEN, DAN M · 2022 to 2025
$8.1MPathogenic hotspots illuminate mechanism and therapeutic potential in arrhythmogenic cardiomyopathyR01HL168059 · NHLBI · STANFORD UNIVERSITY · PI Victoria Parikh · 2023 to 2026
$3.0MhiPSC Modeling of Restrictive Cardiomyopathy for Drug TestingR01HL169340 · NHLBI · STANFORD UNIVERSITY · PI MARK MERCOLA · 2023 to 2026
$2.3MHigh throughput platform for simultaneous multiparametric assessment of cardiac physiology for heart failure drug developmentR33HL167258 · NHLBI · STANFORD UNIVERSITY · PI MERCOLA, MARK · 2023 to 2024
$908kThe Role of RBM20 Sequence and Expression in Dilated CardiomyopathiesK08HL143185 · NHLBI · STANFORD UNIVERSITY · PI PARIKH, VICTORIA · 2019 to 2023
$725kProbing the Molecular Mechanisms of Diastolic Dysfunction Using Patient-Specific Stem CellsK08HL165094 · NHLBI · STANFORD UNIVERSITY · PI David Wells Staudt · 2023 to 2026
$664kACTN4 Binding to Functional SNP rs9277336 Controls the Genome Architecture and Endothelial Pathophenotypes in Pulmonary ArterialF30HL170649 · NHLBI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI Anna Kirillova · 2023 to 2026
$198kNHGRI NIH HHS U01 HG011762NHLBI NIH HHS F30 HL170649NHLBI NIH HHS K08 HL143185NHLBI NIH HHS K08 HL165094NHLBI NIH HHS R01 HL164675NHLBI NIH HHS R01 HL168059NHLBI NIH HHS R01 HL169340NHLBI NIH HHS R33 HL167258
Abstract
backgroundAn 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
methodsWe 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
resultsOur multidimensional mapping strategy enabled high-resolution functional analysis of
conclusionsThis 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.
Indexed as
cardiomyopathy, hypertrophicMYBPC3 protein, humanmyocytes, cardiacRNA splicing
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