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Updated: Apr 1, 2026
Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
Published on: August 8, 2022
Use of high-throughput targeted exome-sequencing to screen for copy number variation in hypertrophic cardiomyopathy
L R Lopes1, C Murphy2, P Syrris3
1Inherited Cardiovascular Disease Unit, Institute of Cardiovascular Science, UCL, London, UK; Cardiovascular Centre, University of Lisbon, Lisbon, Portugal.
Insights
Copy-number variants (CNVs) are rarely a cause of hypertrophic cardiomyopathy (HCM), with only 0.8% of patients in this study having validated CNVs. This study highlights CNVs as a potential, though infrequent, genetic cause of HCM.
Area of Science:
- Genetics
- Cardiology
- Genomic Medicine
Background:
- The genetic underpinnings of hypertrophic cardiomyopathy (HCM) are complex, with copy-number variants (CNVs) being an understudied area.
- Understanding the role of CNVs in HCM is crucial for comprehensive genetic diagnosis.
Purpose of the Study:
- To investigate the prevalence and impact of CNVs in a large cohort of HCM patients.
- To screen for CNVs in known cardiomyopathy-associated genes using high-throughput sequencing (HTS) data.
Main Methods:
- A cohort of 505 unrelated HCM patients underwent HTS for 41 cardiovascular genes.
- A read-depth strategy (ExomeDepth) was employed to identify CNVs from short-read sequencing data.
- Validated CNVs in 19 cardiomyopathy-associated genes using comparative genomic hybridization array.
Main Results:
- Twelve potential CNVs were initially identified.
- Four CNVs were validated in 4 patients (0.8% of the cohort): deletions in MYBPC3 and PDLIM3, and duplications in TNNT2 and LMNA.
- These validated CNVs represent rare genetic causes of HCM.
Conclusions:
- Pathogenic CNVs account for a small proportion (<1%) of HCM cases.
- CNVs have direct clinical implications for a subset of HCM patients.
- HTS data combined with a validation step is an effective strategy for identifying novel genetic causes of HCM.
Introduction:
The role of copy-number variants (CNV) as a cause of hypertrophic cardiomyopathy (HCM) is poorly studied. The aim of this study was to use high-throughput sequence (HTS) data combined with a read-depth strategy, to screen for CNV in cardiomyopathy-associated genes in a large consecutive cohort of HCM patients.
Methods:
Five-hundred-and-five unrelated HCM patients were genotyped using a HTS approach for 41 cardiovascular genes. We used a previously validated read-depth strategy (ExomeDepth) to call CNVs from the short-read sequence data. Detected CNVs in 19 cardiomyopathy-associated genes were then validated by comparative genomic hybridization array.
Results:
Twelve CNVs were identified. Four CNVs in 4 patients (0.8% of the cohort) were validated: one large deletion in MYBPC3, one large deletion in PDLIM3, one duplication of the entire TNNT2 gene and one large duplication in LMNA.
Conclusions:
Our data suggest that the proportion of HCM cases with pathogenic CNVs is small (<1%). For the small subset of patients with clearly interpretable CNVs, our findings have direct clinical implications. Short read sequence data can be used for CNV calling, but the high false positive rate requires a validation step. The two-step strategy described here is effective at identifying novel genetic causes of HCM and similar techniques should be applied whenever possible.
Related Concept Videos
01:29Cardiomyopathy III: Hypertrophic Cardiomyopathy
02:26Comparing Copy Number Variations and SNPs
Copy number variations or CNVs are the structural variations that cover more than 1kb of DNA sequence. The single nucleotide polymorphism (SNP), on the other hand, is a single nucleotide change or a point mutation that is found in more than 1%...