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Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
Published on: August 8, 2022
Molecular autopsy in young sudden cardiac death victims with suspected cardiomyopathy
M K Larsen1, P H Nissen, K E Berge
1Department of Forensic Medicine, Faculty of Health Sciences, Aarhus University, Aarhus N, Denmark. ml@forensic.au.dk
Insights
Pathogenic mutations were identified in 9.8% of young sudden cardiac death (SCD) victims suspected of cardiomyopathy. Genetic screening revealed mutations in genes linked to hypertrophic, dilated, and arrhythmogenic cardiomyopathies.
Area of Science:
- Cardiovascular Genetics
- Forensic Medicine
- Molecular Pathology
Background:
- Sudden cardiac death (SCD) in young individuals (0-40 years) often involves underlying cardiomyopathies.
- Genetic factors play a significant role in the etiology of these heart muscle diseases.
- Comprehensive genetic screening is crucial for understanding SCD mechanisms.
Purpose of the Study:
- To identify and characterize pathogenic mutations in a cohort of young SCD victims with suspected cardiomyopathy.
- To determine the frequency of genetic variants in genes associated with hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and arrhythmogenic right ventricle cardiomyopathy (ARVC).
- To contribute to the understanding of the genetic basis of SCD in the young population.
Main Methods:
- Genetic screening of 41 cases from forensic medicine databases.
- DNA sequencing to detect mutations in key cardiomyopathy-associated genes (MYBPC3, MYH7, LMNA, PKP2, TMEM43).
- Analysis of sequence variants to identify presumed pathogenic mutations.
Main Results:
- Rare sequence variants were found in 9 out of 41 cases (22%).
- Four cases (9.8%) harbored presumed pathogenic mutations.
- Identified mutations included MYH7 (p.R442H) in suspected HCM/DCM, LMNA (p.R471H) in suspected DCM, and PKP2 (p.R79X) and LMNA (p.R644C) in suspected ARVC.
Conclusions:
- Genetic mutations are present in a significant proportion of young SCD victims with suspected cardiomyopathy.
- Molecular autopsy is essential for identifying genetic causes of SCD in post-mortem examinations.
- These findings highlight the importance of genetic evaluation in SCD cases with cardiac structural anomalies.
Abstract:
The aim of this investigation was to identify and characterise pathogenic mutations in a sudden cardiac death (SCD) cohort suspected of cardiomyopathy in persons aged 0-40 years. The study material for the genetic screening of cardiomyopathies consisted of 41 cases and was selected from the case database at the Institute of Forensic Medicine. Mutational screening by DNA sequencing was performed to detect mutations in DNA samples from deceased persons suspected of suffering from hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and arrhythmogenic right ventricle cardiomyopathy (ARVC). A total of 9 of the examined 41 cases had a rare sequence variant in the MYBPC3, MYH7, LMNA, PKP2 or TMEM43 genes, of which 4 cases (9.8%) were presumed to be pathogenic mutations. The presumed pathogenic mutations were distributed with one case of suspected HCM and DCM (MYH7; p.R442H), one case of suspected DCM (LMNA; p.R471H), and two cases of suspected ARVC (PKP2; p.R79X and LMNA; p.R644C). The presented data adds important information on the genetic elements of SCD in the young, and calls for expert pathological evaluation and molecular autopsy in the post-mortem examination of SCD victims with structural anomalies of the heart.
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