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Post-mortem genetic analysis of sudden unexplained death in a young cohort: a whole-exome sequencing study

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Abstract

Sudden unexplained death (SUD) constitutes a considerable portion of unexpected sudden death in the young. Molecular autopsy has proved to be an efficient diagnostic tool in the multidisciplinary management of SUD. Yet, many cases remain undiagnosed using the widely adopted targeted genetic screening strategies. Here, we investigated the genetic substrates of a young SUD cohort (18–40 years old) from China using whole-exome sequencing (WES), with the primary aim to identify novel SUD susceptibility genes. Within 255 previously acknowledged SUD-associated genes, 21 variants with likely functional effects (pathogenic/likely pathogenic) were identified in 51.9% of the SUD cases. More importantly, a set of 33 candidate genes associated with myopathy were identified to be novel susceptibility genes for SUD. Comparative analysis of the cumulative PHRED-scaled CADD score and polygenetic burden score showed that the amount and deleteriousness of variants in the 255 SUD-associated genes and the 33 candidate genes identified by this study were significantly higher compared with 289 randomly selected genes. A significantly higher genetic burden of rare variants (MAF < 0.1%) in the 33 candidate genes also highlighted putative roles of these genes in SUD. After incorporating these novel genes, the genetic testing yields of the current SUD cohort elevated from 51.9 to 66.7%. Our study expands understanding of the genetic variants underlying SUD and presents insights that improve the utility of genetic screenings.

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Data availability

The datasets generated during the current study are available from the first or corresponding authors upon reasonable request.

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Acknowledgements

We thank Dr. Cordula Haas and Dr. Jacqueline Neubauer from the Zurich Institute of Forensic Medicine (University of Zurich, Switzerland) for their guidance on data interpretation. We also feel grateful to Dr. Fanqian Yin from the Kunming Institute of Zoology (Chinese Academy of Sciences, China) for bioinformatics support.

Funding

This study was supported by the National Science Foundation of China (82070285, 82101971 and 82322033), the National Postdoctoral Science Foundation of China (2021M700815), and the Student Scientific Research Program of Shanghai Medical College, Fudan University (QF2203). The authors express their gratitude to the foundations that supported this study.

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Author notes

  1. Shouyu Wang, Yongsheng Chen, and Jianghua Du contributed equally to this work.

Authors and Affiliations

  1. Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, 131 Dongan Road, Xuhui District, Shanghai, 200032, People’s Republic of China

    Shouyu Wang, Jianghua Du, Zhimin Wang, Zijie Lin, Guanghui Hong, Yiwen Shen & Liliang Li

  2. Shanghai Key Laboratory of Crime Scene Evidence, Shanghai Public Security Bureau, Shanghai, 200083, People’s Republic of China

    Yongsheng Chen

  3. Institute of Legal Medicine, Hannover Medical School, 30625, Hannover, Germany

    Dong Qu

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  1. Shouyu Wang
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Correspondence to Liliang Li.

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Ethics approval

Informed consent was obtained from relatives of all individual participants included in the study before sample collection. The use of collected human samples for research purpose was approved by the Institutional Review Board at the School of Basic Medical Sciences, Fudan University (approval No.: 2021-C017). All procedures performed in studies were in accordance with the local ethical standards and principles outlined in the Declaration of Helsinki.

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Supplementary Information

ESM 1

Top 60 pathways and processes clusters identified by enrichment analysis. The p values are calculated based on the cumulative hypergeometric distribution. (PNG 905 kb)

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Canonical pathway, KEGG pathway and GO biological processes identified by enrichment analysis for the 20 myopathy-associated genes. (PNG 1647 kb)

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Significant differences of polygenetic burden scores (the black dots) observed among groups (***p < 0.001). In addition, the amount of rare variants within exonic or splicing region in Group S (374) and Group C (266) was higher compared with Group R (208). (PNG 57 kb)

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Wang, S., Chen, Y., Du, J. et al. Post-mortem genetic analysis of sudden unexplained death in a young cohort: a whole-exome sequencing study. Int J Legal Med 137, 1661–1670 (2023). https://doi.org/10.1007/s00414-023-03075-1

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