Skip to content
DraconiticResearch
Search Sources API
186,086 studies31 sourcesUpdated 13 min ago
Peer-reviewedCC BY-NC-ND 4.0Circulation

Scaled Multidimensional Assays of Variant Effect Identify Sequence-Function Relationships in Hypertrophic Cardiomyopathy

  • Yuta Yamamoto1
  • Kaiser Chua1
  • David Staudt1,2
  • Alexis Ferrasse1
  • Anna Kirillova3
  • Hannah N. De Jong4
  • Brendan J. Floyd1,2
  • Christian Cadisch1,5
  • Laurens Wiel1
  • Qianru Wang1,6
  • Matthew J. O’Neill7
  • Daniel Tabet8
15 more authors
  • John E. Goryznski1,4
  • Yong Huang1
  • Fang Bai1
  • Rachel H. Wilson1
  • Arman Sharma1
  • Althea Tapales1,9
  • Rani Agrawal1
  • Matthew T. Wheeler1
  • Mark Mercola1,10
  • Calum A. MacRae7
  • Dan M. Roden11,12,13
  • Frederick P. Roth8,14
  • Andrew M. Glazer11
  • Euan A. Ashley1
  • Victoria N. Parikh1
14 affiliations
  1. 1Stanford 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.
  2. 2Department of Pediatrics (D.S., B.J.F.), Stanford School of Medicine, Palo Alto, CA.
  3. 3Medical Scientist Training Program, University of Pittsburgh, PA (A.K.).
  4. 4Department of Genetics (H.N.D.J., J.E.G.), Stanford School of Medicine, Palo Alto, CA.
  5. 5ETH Zurich, Switzerland (C.C.).
  6. 6School of Biomedical Engineering, Shanghai Jiao Tong University, China (Q.W.).
  7. 7Brigham and Women’s Hospital, HMS, Boston, MA (M.J.O., C.A.M.).
  8. 8Donnelly Centre and Department of Molecular Genetics, University of Toronto, ON, Canada (D.T., F.P.R.).
  9. 9University of Vermont, Larner College of Medicine, Burlington (A.T.).
  10. 10Department of Medicine, Department of Chemical and Systems Biology, and Cardiovascular Institute, Stanford University, Palo Alto, CA (M.M.).
  11. 11Department of Medicine, Division of Genomic Medicine and Clinical Pharmacology (D.M.R., A.M.G.), Vanderbilt University Medical Center, Nashville, TN.
  12. 12Department of Pharmacology (D.M.R.), Vanderbilt University Medical Center, Nashville, TN.
  13. 13Department of Biomedical Informatics (D.M.R.), Vanderbilt University Medical Center, Nashville, TN.
  14. 14Department of Computational and Systems Biology, University of Pittsburgh School of Medicine ; PA (F.P.R.).
Read full textDOICite

Abstract

BACKGROUND:: 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 MYBPC3 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.

METHODS:: 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 MYBPC3 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–derived cardiomyocytes.

RESULTS:: Our multidimensional mapping strategy enabled high-resolution functional analysis of MYBPC3 variants in induced pluripotent stem cell–derived 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 MYBPC3 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.

CONCLUSIONS:: 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.

Related

  1. A late bloom at the apex: development of apical hypertrophic cardiomyopathy phenotype in advanced age
    European heart journal. Case reportsPeer-reviewedCC BYFull textCardiovascular medicineEurope PMC
  2. Research trends and hotspot analysis of sudden cardiac death in hypertrophic cardiomyopathy : A bibliometric analysis
    Zhen Chen, Fen Ai, Jinlei Li +1
    MedicinePeer-reviewedCC BYFull textGeneral medicineEurope PMC
  3. Managing a mavacamten non-responder in obstructive hypertrophic cardiomyopathy: A case report
    Smita Scholtz, Felix Langkamp, Volker Rudolph +2
    Journal of cardiology casesPeer-reviewedCC BYFull textCardiovascular medicineEurope PMC
  4. Percutaneous endomyocardial ablation as a septal reduction strategy in symptomatic obstructive hypertrophic cardiomyopathy: A 20-year single-center observational experience.
    Aoife Casey, John McCormick, David Keane
    HeartRhythm case reportsPeer-reviewedCC BYFull textCardiovascular medicineEurope PMC
  5. Transatrial air-assisted epicardial ventricular tachycardia ablation for hypertrophic cardiomyopathy and management of postprocedural right atrial thrombus.
    İbrahim Etem Dural, Mehmet Özgeyik, Ramazan Anıl Eşki +1
    HeartRhythm case reportsPeer-reviewedCC BY-NC-NDFull textCardiovascular medicineEurope PMC

Cite

BibTeXRIS
BibTeX
@article{yamamoto2026scaled,
  title = {{Scaled Multidimensional Assays of Variant Effect Identify Sequence-Function Relationships in Hypertrophic Cardiomyopathy}},
  author = {Yuta Yamamoto and Kaiser Chua and David Staudt and Alexis Ferrasse and Anna Kirillova and Hannah N. De Jong and Brendan J. Floyd and Christian Cadisch and Laurens Wiel and Qianru Wang and Matthew J. O’Neill and Daniel Tabet and John E. Goryznski and Yong Huang and Fang Bai and Rachel H. Wilson and Arman Sharma and Althea Tapales and Rani Agrawal and Matthew T. Wheeler and Mark Mercola and Calum A. MacRae and Dan M. Roden and Frederick P. Roth and Andrew M. Glazer and Euan A. Ashley and Victoria N. Parikh},
  journal = {Circulation},
  year = {2026},
  month = jul,
  doi = {10.1161/circulationaha.125.075535},
  url = {https://doi.org/10.1161/circulationaha.125.075535},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Scaled Multidimensional Assays of Variant Effect Identify Sequence-Function Relationships in Hypertrophic Cardiomyopathy
AU  - Yuta Yamamoto
AU  - Kaiser Chua
AU  - David Staudt
AU  - Alexis Ferrasse
AU  - Anna Kirillova
AU  - Hannah N. De Jong
AU  - Brendan J. Floyd
AU  - Christian Cadisch
AU  - Laurens Wiel
AU  - Qianru Wang
AU  - Matthew J. O’Neill
AU  - Daniel Tabet
AU  - John E. Goryznski
AU  - Yong Huang
AU  - Fang Bai
AU  - Rachel H. Wilson
AU  - Arman Sharma
AU  - Althea Tapales
AU  - Rani Agrawal
AU  - Matthew T. Wheeler
AU  - Mark Mercola
AU  - Calum A. MacRae
AU  - Dan M. Roden
AU  - Frederick P. Roth
AU  - Andrew M. Glazer
AU  - Euan A. Ashley
AU  - Victoria N. Parikh
PY  - 2026
DA  - 2026/07/12
JO  - Circulation
DO  - 10.1161/circulationaha.125.075535
UR  - https://doi.org/10.1161/circulationaha.125.075535
AB  - BACKGROUND:: 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 MYBPC3 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.  METHODS:: 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 MYBPC3 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–derived cardiomyocytes.  RESULTS:: Our multidimensional mapping strategy enabled high-resolution functional analysis of MYBPC3 variants in induced pluripotent stem cell–derived 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 MYBPC3 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.  CONCLUSIONS:: 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.
SN  - 0009-7322
SN  - 1524-4539
ER  -