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Postmortem genetic analysis of 17 sudden cardiac deaths identified nonsense and frameshift variants in two cases of arrhythmogenic cardiomyopathy

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Abstract

Sudden death, or unexpected natural death of a healthy individual, is a serious problem in all nations. Sudden cardiac death (SCD) mainly due to ischemic heart diseases is the top cause of sudden death. However, there are pathophysiological conditions, referred to as sudden arrhythmic death syndrome, in which no apparent lesion can be identified even after complete conventional or ordinary autopsy. While postmortem genetic analyses have accumulated evidence about underlying genetic abnormality in such cases, the precise relationships between genetic background and the phenotype have been largely elusive. In this study, a retrospective investigation of 17 autopsy cases in which lethal arrhythmia was suspected to be the cause of death was carried out. Genetic analysis focusing on 72 genes reported to be associated with cardiac dysfunctions was performed, in combination with detailed histopathological and postmortem imaging examination, and a family study. As a result, in two cases of suspected arrhythmogenic cardiomyopathy (ACM), we found a nonsense variant in PKP2 and frameshift variant in TRPM4 gene. In contrast, the other 15 cases showed no morphological changes in the heart despite the presence of a frameshift variant and several missense variants, leaving the clinical significance of these variants obscure. The findings of the present study suggest that nonsense and frameshift variants could be involved in the morphological abnormality in cases of SCD due to ACM, while missense variants alone rarely contribute to massive structural changes in the heart.

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Data availability

The raw DNA sequence data generated during the current study are not publicly available since they could potentially identify a specific individual. But they are available from the corresponding author upon reasonable request and with permission of the Ethics Committee at Gunma University Graduate School of Medicine.

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Acknowledgements

We are thankful to Tomoko Miwa and Megumi Harada for their help with conducting autopsy, performing genetic analysis, and preparing this manuscript. We are also thankful to Kouichi Ujita for his help with capturing MRI images of the heart. We thank Yohei Morishita, Saori Umezawa, Yuichi Uosaki, Yoko Yokoyama, Hiroko Matsuda, and Saori Fujimoto for their technical assistance for NGS analysis. We are indebted to Thomas Mayers, Medical English Communications Center, University of Tsukuba, for grammatical revision of this paper. This work was supported by the Fostering Health Professionals for Changing Needs of Cancer by MEXT of Japan and Gunma University Initiative for Advanced Research (GIAR).

Funding

This work was supported in part by JSPS KAKENHI Grant Numbers 22K10601 to Y.T., 20K18977 to A.H., 20K10551 to R.S., 18K10118 to R.K., 20K10550 to H.T.[Tokue], and 19H03916 to Y.K. This work was the result of using research equipment shared in the MEXT Project for promoting public utilization of advanced research infrastructure (Program for supporting the introduction of the new sharing system): Grant Number JPMXS0420600120.

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Authors and Affiliations

  1. Department of Legal Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan

    Yoichiro Takahashi, Haruki Fukuda, Akira Hayakawa, Rie Sano, Rieko Kubo & Yoshihiko Kominato

  2. Department of Legal Medicine, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan

    Yoichiro Takahashi, Tomohiro Seki, Yi-Yang Hsiao & Fujio Ishizawa

  3. Division of Integrated Oncology Research, Gunma University Initiative for Advanced Research, Gunma University, Maebashi, Japan

    Reika Kawabata-Iwakawa

  4. Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan

    Tadashi Nakajima

  5. Department of Pediatrics, Gunma University Graduate School of Medicine, Maebashi, Japan

    Takashi Ishige

  6. Department of Diagnostic Radiology & Nuclear Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan

    Hiroyuki Tokue

  7. Department of Radiology, Gunma University Hospital, Maebashi, Japan

    Kazuya Asano & Hiroyuki Takei

  8. Faculty of Health Sciences, Tsukuba International University, Tsuchiura, Japan

    Hiroyuki Takei

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  1. Yoichiro Takahashi
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Contributions

Y.T. designed the study, collected samples, analyzed the data, and wrote the manuscript. H.F., A.H. and R.S. collected samples. R.K. and R.K-I. performed genetic analysis. T.N. and T.I. coordinated family study. H.T.[Tokue], K.A., and H.T.[Takei] performed postmortem imaging. T.S., Y-Y.H., and F.I. analyzed the data. Y.K. designed the study and wrote the manuscript. All the authors read and approved the final manuscript.

Corresponding author

Correspondence to Yoichiro Takahashi.

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All procedures of this study were approved by the Ethics Committee at Gunma University Graduate School of Medicine (No. HS2017-015) and were performed in accordance with the committee guidelines and regulations.

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Written informed consent was obtained from legal guardians or close family members if contact could be made. If there were no legal guardians with whom we were able to contact, inform consent was waived by with the Ethics Committee at Gunma University, Graduate School of Medicine (No. HS2017-015).

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The authors declare no competing interests.

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Takahashi, Y., Fukuda, H., Hayakawa, A. et al. Postmortem genetic analysis of 17 sudden cardiac deaths identified nonsense and frameshift variants in two cases of arrhythmogenic cardiomyopathy. Int J Legal Med 137, 1927–1937 (2023). https://doi.org/10.1007/s00414-023-03037-7

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