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Related Concept Videos

Cardiomyopathy III: Hypertrophic Cardiomyopathy01:29

Cardiomyopathy III: Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy, or HCM, is an autosomal dominant genetic disorder characterized by asymmetric left ventricular hypertrophy without ventricular dilation. It is more common in men and is typically diagnosed in young, athletic adults.EtiologyHCM is primarily genetic and is caused by mutations in genes encoding sarcomeric proteins. Researchers have identified over 1400 mutations across at least 11 different genes. Among these, the most frequently occurring mutations are found in the...
Cardiomyopathy II: Dilated Cardiomyopathy01:30

Cardiomyopathy II: Dilated Cardiomyopathy

Dilated cardiomyopathy, or DCM, is a progressive myocardial disorder characterized by ventricular chamber dilation and contractile dysfunction.EtiologyVarious factors can cause DCM, including hypertension and heavy alcohol intake, which contribute to the weakening and enlargement of the heart muscle. Viral infections, such as Coxsackievirus B, adenoviruses, and influenza, can lead to DCM by causing inflammation and damage to heart tissue. Certain chemotherapeutic agents, including daunorubicin,...

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Related Experiment Video

Updated: Jul 13, 2026

Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
03:45

Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model

Published on: August 8, 2022

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

Yuta Yamamoto1, Kaiser Chua1, David Staudt1,2

  • 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.

Circulation
|July 12, 2026
PubMed
Summary

Genetic variants in MYBPC3 cause hypertrophic cardiomyopathy (HCM). This study developed a new method to interpret these variants, revealing decreased cardiac myosin-binding protein C (cMyBP-C) abundance as a key driver of HCM and identifying new disease mechanisms.

Keywords:
MYBPC3 protein, humanRNA splicingcardiomyopathy, hypertrophicmyocytes, cardiac

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Last Updated: Jul 13, 2026

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Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
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Published on: January 16, 2019

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Published on: November 2, 2020

Area of Science:

  • Cardiovascular Genetics
  • Molecular Cardiology
  • Genomic Medicine

Background:

  • Hypertrophic cardiomyopathy (HCM) affects 1 in 500 people, with genetic diagnosis aiding risk identification and therapy.
  • MYBPC3 gene variants are a major cause of HCM, but many variants of uncertain significance complicate clinical decisions.
  • Scalable methods for interpreting genetic variants in relevant cell types are crucial for understanding disease mechanisms.

Purpose of the Study:

  • To develop a scalable, multidimensional mapping strategy for evaluating the functional impact of MYBPC3 variants.
  • To analyze variant effects on cardiac myosin-binding protein C (cMyBP-C) function and HCM-relevant phenotypes in patient-derived cells.
  • To improve the interpretation of MYBPC3 variants and uncover novel disease mechanisms.

Main Methods:

  • Developed a multidimensional mapping strategy using saturation base editing at the native MYBPC3 locus.
  • Employed a long-read RNA sequencing assay to assess variant splice effects.
  • Measured HCM-relevant phenotypes in human induced pluripotent stem cell-derived cardiomyocytes, including cMyBP-C abundance and hypertrophic signaling.

Main Results:

  • High-resolution functional analysis of MYBPC3 variants in cardiomyocytes was achieved.
  • A massively parallel splicing assay identified novel splice-disrupting variants.
  • Decreased cMyBP-C abundance was identified as a key driver of HCM phenotypes, with protein degradation downregulation correlating with MYBPC3 loss of function.

Conclusions:

  • The developed platform enables multiplexed assays of variant effects across diverse cellular phenotypes using genome engineering.
  • This approach enhances understanding of variant pathogenicity and uncovers novel biological mechanisms for HCM.
  • Findings can inform therapeutic strategies for hypertrophic cardiomyopathy.