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Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
Published on: August 8, 2022
A DNA resequencing array for pathogenic mutation detection in hypertrophic cardiomyopathy
Siv Fokstuen1, Robert Lyle, Analia Munoz
1Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland. siv.fokstuen@medecine.unige.ch
Insights
Hypertrophic cardiomyopathy (HCM) is a genetic heart condition. A new DNA resequencing array efficiently detects mutations in HCM-linked genes, aiding diagnosis and patient stratification.
Area of Science:
- Genetics
- Cardiology
- Molecular Biology
Background:
- Hypertrophic cardiomyopathy (HCM) is an autosomal dominant cardiac disorder affecting 1 in 500 individuals.
- Over 450 mutations in at least 16 genes are linked to HCM, necessitating efficient genetic testing.
- The genetic heterogeneity of HCM poses challenges for clinical molecular screening.
Purpose of the Study:
- To develop a high-throughput, rapid, and cost-effective DNA resequencing array for detecting mutations in HCM-associated genes.
- To assess the utility of this custom array in a cohort of patients with hypertrophic cardiomyopathy.
- To evaluate the potential of the array for diagnostic, predictive, and prognostic applications in HCM.
Main Methods:
- A custom DNA resequencing array was designed to cover coding exons, splice junctions, and 5'UTR regions of 12 key HCM genes.
- The array was used to analyze DNA from 38 unrelated HCM patients (17 familial, 21 sporadic).
- Sequencing data across 953,306 bp were analyzed for pathogenic mutations.
Main Results:
- Pathogenic mutations (known and novel) in MYH7, MYBPC3, TNNI3, and MYL3 were identified in 60% of familial HCM cases and 10% of sporadic cases.
- The resequencing array demonstrated a high mean nucleotide call rate of 96.92%.
- The array successfully identified mutations in key genes implicated in hypertrophic cardiomyopathy.
Conclusions:
- The developed high-throughput HCM resequencing array is a rapid and cost-effective tool for molecular testing.
- This technology has significant potential for improving diagnostic accuracy, predictive testing, and prognostic stratification in HCM patients.
- The array facilitates the integration of molecular screening into clinical practice for hypertrophic cardiomyopathy.
Abstract:
Hypertrophic cardiomyopathy (HCM) is a heterogeneous autosomal dominant cardiac disorder with a prevalence of 1 in 500. Over 450 different pathogenic mutations in at least 16 genes have been identified so far. The large allelic and genetic heterogeneity of HCM requires high-throughput, rapid, and affordable mutation detection technologies to efficiently integrate molecular screening into clinical practice. We developed a custom DNA resequencing array that contains both strands of all coding exons (160), splice-site junctions, and 5'UTR regions of 12 genes that have been clearly implicated in HCM (MYH7, MYBPC3, TNNT2, TPM1, TNNI3, MYL3, MYL2, CSRP3, PLN, ACTC, TNNC1, and PRKAG2). We analyzed a first series of 38 unrelated patients with HCM (17 familial, 21 sporadic). A total of 953,306 bp across the 38 patients were sequenced with a mean nucleotide call rate of 96.92% (range: 93-99.9%). Pathogenic mutations (single nucleotide substitutions) in MYH7, MYBPC3, TNNI3, and MYL3 (six known and six novel) were identified in 60% (10/17) of familial HCM and 10% of sporadic cases (2/21). The high-throughput HCM resequencing array is the most rapid and cost-effective tool for molecular testing of HCM to date; it thus has considerable potential in diagnostic and predictive testing, and prognostic stratification.
