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Abstract：
The aim of this study is to determine the molecular mechanism of sudden death in a previously healthy patient. Clinical exome sequencing revealed I536T-RBM20 variant, which alters RNA splicing of TTN and is causative for dilated cardiomyopathy. Comprehensive RNA sequencing (RNA-seq) was also performed in the patient samples and the control samples. Splicing abnormality was compared in cardiac muscle and skeletal muscle. RNA-seq analysis of the cardiac and skeletal muscle showed abnormal splicing of LDB3, not of TTN. Exon 11 of LDB3 was abnormally included in the patient samples compared with the control samples. This abnormal LDB3 splicing pattern in skeletal muscle has been reported in myotonic dystrophy type 1 (DM1) patients. We, thus, confirmed that the patient had expanded CTG repeat in DMPK and the diagnosis was genetically DM1. This finding suggest that one of the molecular mechanisms of sudden cardiac death in this asymptomatic subclinical DM1 patient might be LDB3 abnormal splicing due to the CTG repeat in DMPK, rather than RBM20 variant. RNA-seq analysis is useful to determine the exact molecular diagnosis for sudden cardiac death.
摘要：
这项研究的目的是确定先前健康患者猝死的分子机制。临床外显子组测序显示I536T-RBM20变异体，它改变了TTN的RNA剪接，是扩张型心肌病的病因。还在患者样品和对照样品中进行了综合RNA测序(RNA-seq)。比较心肌和骨骼肌的剪接异常。心脏和骨骼肌的RNA-seq分析显示LDB3而不是TTN的异常剪接。与对照样品相比,患者样品中异常包括LDB3的外显子11。已经在1型肌强直性营养不良（DM1）患者中报道了骨骼肌中这种异常的LDB3剪接模式。我们,因此，证实患者在DMPK中CTG重复序列扩大,诊断为基因DM1.这一发现表明，该无症状的亚临床DM1患者心脏猝死的分子机制之一可能是由于DMPK中的CTG重复序列引起的LDB3异常剪接，而不是RBM20变体。RNA-seq分析可用于确定心脏猝死的确切分子诊断。
