Postmortem genetic analysis of sudden unexplained death syndrome under 50 years of age: A next-generation sequencing study

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• 作者：Yukiko Hata ; PhD^* ; Koshi Kinoshita ; PhD^* ; Koichi Mizumaki ; MD ; PhD^&dagger ; ; Yoshiaki Yamaguchi ; MD ; PhD^&Dagger ; ; Keiichi Hirono ; MD ; PhD^§ ; ; Fukiko Ichida ; MD ; PhD^§ ; ; Asami Takasaki ; MD^§ ; ; Hisashi Mori ; PhD^¶ ; ; Naoki Nishida ; MD ; PhD^* ; ^{nishida@med.u-toyama.ac.jp" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Arrhythmogenic right ventricular cardiomyopathy ; Autopsy ; Cardiomyopathy ; Channelopathy ; Next-generation sequencing ; Pathology ; Sudden unexplained death syndrome
• 刊名：Heart Rhythm
• 出版年：2016
• 出版时间：July 2016
• 年：2016
• 卷：13
• 期：7
• 页码：1544-1551
• 全文大小：3085 K

文摘

Recent studies on the genetic analysis of victims of sudden unexplained death syndrome (SUDS) have shown diagnostic potential. Previously, such analyses mainly targeted the major channelopathy-associated genes.

Objective

The purpose of this study was to evaluate the utility of next-generation sequencing (NGS) in the postmortem diagnosis of SUDS.

Methods

Our data are derived from 25 cases of SUDS (21 men and 4 women; age 19–50 years). A total of 70 genes were examined by NGS, and the pathogenicity of any detected rare variants with minor allele frequencies of <0.5% was evaluated using a widely used database and eight in silico algorithms.

Results

Five known and 15 potentially pathogenic variants with a high in silico score were identified in 14 cases. In all, 6 channelopathy-related variants were identified in 5 cases, including 2 cases with history of arrhythmia; 11 cases had cardiomyopathy- or cardiac transcription factor-related variants. Three cases with desmosomal gene- or other cardiomyopathy-related variants showed possibly related pathologic changes. Three cases with RYR2 or TBX5 variants showed possible pathogenic fibrosis of the cardiac conduction system. Only 12 variants showed moderate or strong possible pathogenicity in SUDS cases compared with qualifying controls.

Conclusion

Hereditary heart diseases other than channelopathy may also be a significant cause of SUDS, even if clinical and pathologic findings do not show advanced disease. A combination of gene analysis using NGS and some predictive methods for detecting variants and careful pathologic evaluation may provide a reliable diagnosis of hereditary heart disease for potential SUDS cases.