RNA sequencing reveals abnormal LDB3 splicing in sudden cardiac death

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.