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Updated: Jun 11, 2025
Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
Published on: August 8, 2022
Reanalysis of Next-generation Sequencing Data in Patients With Hypertrophic Cardiomyopathy: Contribution of
Silvia Caroselli1,2, Marco Fabiani1,3, Caterina Micolonghi1
1Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
Insights
Improved bioinformatics analysis identified rare intronic variants in the MYBPC3 gene, increasing the diagnostic yield for hypertrophic cardiomyopathy (HCM). This finding highlights the importance of detecting these variants for comprehensive genetic testing in HCM patients.
Area of Science:
- Genetics
- Cardiology
- Bioinformatics
Background:
- Hypertrophic cardiomyopathy (HCM) is a heterogeneous genetic cardiac disease.
- Current genetic testing has limitations, failing to identify causative variants in 40-60% of cases.
- Intronic variants, particularly in MYBPC3, are often missed by standard diagnostic panels.
Purpose of the Study:
- To enhance the diagnostic yield of molecular analysis for HCM.
- To improve the in-silico detection of intronic variants in MYBPC3.
- To identify pathogenic variants missed by standard exome sequencing panels.
Main Methods:
- Re-analysis of raw sequencing data from 142 HCM probands with prior negative genetic testing results.
- Utilized bioinformatics tools to detect intronic variants, focusing on the MYBPC3 gene.
- Included patients previously tested with the Illumina TruSight Cardio panel.
Main Results:
- A spliceogenic intronic variant (c.1224-80G>A) in MYBPC3 was identified in 3 patients (2.1%).
- These patients presented with late-onset, mild HCM symptoms.
- The detected variants led to a re-evaluation and confirmation of the molecular diagnosis.
Conclusions:
- Rare spliceogenic MYBPC3 variants contribute to HCM pathogenesis.
- Systematic detection of intronic variants is crucial for comprehensive HCM genetic testing.
- Improved bioinformatics approaches can increase the diagnostic yield of multigene panels for HCM.
Abstract:
Hypertrophic cardiomyopathy (HCM) is a genetic cardiac muscle disease characterized by clinical and genetic heterogeneity. Genetic testing can reveal the presence of disease-causing variants in genes encoding sarcomere proteins. However, it yields inconclusive or negative results in 40-60% of HCM cases, owing to, among other causes, technical limitations such as the inability to detect pathogenic intronic variants. Therefore, we aimed to increase the diagnostic yield of molecular analysis for HCM by improving the in-silico detection of intronic variants in MYBPC3 that may escape detection by algorithms normally used with tagged diagnostic panels. We included 142 HCM probands with negative results in Illumina TruSight Cardio panel analysis, including exonic regions of 174 cardiomyopathy genes. Raw data were re-analyzed using existing bioinformatics tools. The spliceogenic variant c.1224-80G>A was detected in three patients (2.1%), leading us to reconsider their molecular diagnosis. These patients showed late onset and mild symptoms, although no peculiar phenotypic characteristics were shared. Collectively, rare spliceogenic MYBPC3 variants may play a role in causing HCM, and their systematic detection should be performed to provide more comprehensive solutions in genetic testing using multigenic panels.
