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Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
Published on: August 8, 2022
Rapid detection of genetic variants in hypertrophic cardiomyopathy by custom DNA resequencing array in clinical
Siv Fokstuen1, Analia Munoz, Paola Melacini
1Genetic Medicine, Centre Médical Universitaire, 1 rue Michel-Servet, Geneva, Switzerland. siv.fokstuen@unige.ch
Insights
A custom DNA resequencing array identified pathogenic mutations in 31% of hypertrophic cardiomyopathy (HCM) patients, offering a rapid and cost-effective screening method for this common inherited cardiac disease.
Area of Science:
- Genetics and Genomics
- Cardiovascular Medicine
- Molecular Diagnostics
Background:
- Hypertrophic cardiomyopathy (HCM) is a prevalent inherited cardiac disease affecting 1 in 500 individuals, serving as a leading cause of sudden cardiac death in young populations.
- Accurate detection of pathogenic mutations in HCM significantly influences patient and family management strategies.
- The genetic complexity and allelic diversity of HCM pose challenges for conventional molecular diagnostic methods, rendering them time-consuming and costly for routine laboratory use.
Purpose of the Study:
- To evaluate a custom DNA resequencing array for efficient and cost-effective mutation screening in patients diagnosed with hypertrophic cardiomyopathy (HCM).
- To assess the diagnostic yield of the array in identifying known and novel pathogenic variants across key HCM-associated genes.
Main Methods:
- Development and application of a custom DNA resequencing array targeting all single-nucleotide variants in exons, splice sites, and 5'-untranslated regions of 12 HCM-related genes (totaling 27,000 nucleotides).
- Analysis of DNA samples from 122 unrelated patients with a confirmed diagnosis of HCM.
Main Results:
- The resequencing array successfully identified 33 known or potentially pathogenic heterozygous single-nucleotide variants.
- Pathogenic variants were detected in 38 out of 122 patients (31% prevalence), located in genes including MYH7, MYBPC3, TNNT2, TNNI3, TPM1, MYL3, and ACTC1.
- The identified variants included both previously reported and novel mutations associated with HCM.
Conclusions:
- The custom HCM resequencing array represents a rapid, cost-effective, and efficient first-tier technology for mutation screening in clinical practice, despite the anticipated future dominance of next-generation sequencing.
- The array's design makes it suitable for the initial screening of other inherited forms of cardiomyopathy, broadening its clinical utility.
- This approach facilitates improved genetic diagnosis and management for individuals affected by inherited cardiac disorders.
Background:
Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease (1/500) and the most common cause of sudden cardiac death in young people. Pathogenic mutation detection of HCM is having a growing impact on the medical management of patients and their families. However, the remarkable genetic and allelic heterogeneity makes molecular analysis by conventional methods very time-consuming, expensive and difficult to realise in a routine diagnostic molecular laboratory.
Method And Results:
The authors used their custom DNA resequencing array which interrogates all possible single-nucleotide variants on both strands of all exons (n=160), splice sites and 5'-untranslated region of 12 HCM genes (27 000 nucleotides). The results for 122 unrelated patients with HCM are presented. Thirty-three known or novel potentially pathogenic heterozygous single-nucleotide variants were identified in 38 patients (31%) in genes MYH7, MYBPC3, TNNT2, TNNI3, TPM1, MYL3 and ACTC1.
Conclusions:
Although next-generation sequencing will replace all large-scale sequencing platforms for inherited cardiac disorders in the near future, this HCM resequencing array is currently the most rapid, cost-effective and reasonably efficient technology for first-tier mutation screening of HCM in clinical practice. Because of its design, the array is also an appropriate tool for initial screening of other inherited forms of cardiomyopathy.
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