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Post-mortem genetic investigation in sudden cardiac death victims: complete exon sequencing of forty genes using next-generation sequencing

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Abstract

Sudden cardiac death (SCD) in young people is predominantly caused by genetic causes as cardiomyopathies. Hypertrophic cardiomyopathy is the most common genetic cardiovascular disease and is responsible for the major proportion of SCD in the young. The purpose of this study was to identify the genetic variants present in young SCD victims with HCM characteristics. From the Portuguese records of autopsies performed at the National Institute of Legal Medicine and Forensic Sciences, North Delegation, 16 young (16–50 years) SCD victims whose death was suspected to be a manifestation of HCM were selected. Using next-generation sequencing, the coding regions of 40 genes associated with HCM, candidates, or strongly related to HCM-phenocopies were investigated. The victims included in this study were all males, with a mean age of 33.4 ± 11.7 years, left ventricle mean thickness of 21.5 ± 6.28 mm, and the majority of deaths occurred during sleep (36%). A pathogenic or likely pathogenic variant was identified in six out of 16 (37.5%) victims, in the most common HCM genes (MYBPC3 and MYH7). Our results indicate that molecular autopsy of SCD victims contributes to a more precise identification of a cause of death, and this can be used in the prevention of SCD cases through family screening of first relatives who may carry the same pathogenic variant.

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Data availability

The data that support the findings of this study are available from the corresponding author, J.F., on reasonable request.

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Funding

This work received financial support from PT national funds (FCT/MCTES, Fundação para a Ciência e Tecnologia and Ministério da Ciência, Tecnologia e Ensino Superior) through the project UIDB/50006/2020.

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Authors and Affiliations

  1. Department of Public Health, Forensic Sciences and Medical Education, Faculty of Medicine, University of Porto (FMUP), Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal

    Jennifer Fadoni, Agostinho Santos & Laura Cainé

  2. LAQV&REQUIMTE, Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313, Porto, Portugal

    Jennifer Fadoni, Agostinho Santos & Laura Cainé

  3. National Institute of Legal Medicine and Forensic Sciences, I.P., Centre Branch, Polo das Ciências de Saúde (Polo III), Azinhaga de Santa Comba, 3000-548, Coimbra, Portugal

    Agostinho Santos & Laura Cainé

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  1. Jennifer Fadoni
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  3. Laura Cainé
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Correspondence to Jennifer Fadoni.

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All procedures performed involving human participants were approved by the Investigation, Formation and Documentation Department of the National Institute of Legal Medicine and Forensic Sciences—Portugal and were in accordance with the ethical standards of the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Fig. S1

Outline of the selection procedure of young SCD victims with HCM characteristics (PNG 66 kb)

High resolution image (TIF 162 kb)

Fig. S2

Summary of the NGS laboratory analysis workflow (PNG 76 kb)

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Fadoni, J., Santos, A. & Cainé, L. Post-mortem genetic investigation in sudden cardiac death victims: complete exon sequencing of forty genes using next-generation sequencing. Int J Legal Med 136, 483–491 (2022). https://doi.org/10.1007/s00414-021-02765-y

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