Inherited Metabolic Disease and Sudden Unexplained Death in Infancy and Childhood: Pathophysiology

Sudden cardiac death (SCD) is a diagnostic challenge in forensic medicine. In a relatively large proportion of the SCDs, the deaths remain unexplained after autopsy. This challenge is likely caused by unknown disease mechanisms. Changes in DNA methylation have been associated with several heart diseases, but the role of DNA methylation in SCD is unknown. In this study, we investigated DNA methylation in two SCD subtypes, sudden unexplained death (SUD) and sudden unexpected death in epilepsy (SUDEP). We assessed DNA methylation of more than 850,000 positions in cardiac tissue from nine SUD and 14 SUDEP cases using the Illumina Infinium MethylationEPIC BeadChip. In total, six differently methylated regions (DMRs) between the SUD and SUDEP cases were identified. The DMRs were located in proximity to or overlapping genes encoding proteins that are a part of the glutathione S-transferase (GST) superfamily. Whole genome sequencing (WGS) showed that the DNA methylation alterations were not caused by genetic changes, while whole transcriptome sequencing (WTS) showed that DNA methylation was associated with expression levels of the GSTT1 gene. In conclusion, our results indicate that cardiac DNA methylation is similar in SUD and SUDEP, but with regional differential methylation in proximity to GST genes.

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Postmortem Molecular Screening for Cardiac Ryanodine Receptor Type 2 Mutations in Sudden Unexplained Death

Circulation Journal ◽

10.1253/circj.70.1402 ◽

2006 ◽

Vol 70 (11) ◽

pp. 1402-1406 ◽

Cited By ~ 32

Author(s):

Hajime Nishio ◽

Misa Iwata ◽

Koichi Suzuki

Keyword(s):

Ryanodine Receptor ◽

Receptor Type ◽

Molecular Screening ◽

Sudden Unexplained Death ◽

Unexplained Death ◽

Cardiac Ryanodine Receptor

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Organ transplantation for inherited metabolic disease.

Archives of Disease in Childhood ◽

10.1136/adc.71.3.181 ◽

1994 ◽

Vol 71 (3) ◽

pp. 181-183 ◽

Cited By ~ 9

Author(s):

D A Kelly

Keyword(s):

Metabolic Disease ◽

Organ Transplantation ◽

Inherited Metabolic Disease

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Re-evaluation of single nucleotide variants and identification of structural variants in a cohort of 45 sudden unexplained death cases

International Journal of Legal Medicine ◽

10.1007/s00414-021-02580-5 ◽

2021 ◽

Author(s):

Jacqueline Neubauer ◽

Shouyu Wang ◽

Giancarlo Russo ◽

Cordula Haas

Keyword(s):

Sudden Death ◽

Cardiac Diseases ◽

Structural Variants ◽

Single Nucleotide Variants ◽

Single Nucleotide ◽

Sudden Unexplained Death ◽

Unexplained Death ◽

Pathogenic Variants ◽

The Impact ◽

Death Cases

AbstractSudden unexplained death (SUD) takes up a considerable part in overall sudden death cases, especially in adolescents and young adults. During the past decade, many channelopathy- and cardiomyopathy-associated single nucleotide variants (SNVs) have been identified in SUD studies by means of postmortem molecular autopsy, yet the number of cases that remain inconclusive is still high. Recent studies had suggested that structural variants (SVs) might play an important role in SUD, but there is no consensus on the impact of SVs on inherited cardiac diseases. In this study, we searched for potentially pathogenic SVs in 244 genes associated with cardiac diseases. Whole-exome sequencing and appropriate data analysis were performed in 45 SUD cases. Re-analysis of the exome data according to the current ACMG guidelines identified 14 pathogenic or likely pathogenic variants in 10 (22.2%) out of the 45 SUD cases, whereof 2 (4.4%) individuals had variants with likely functional effects in the channelopathy-associated genes SCN5A and TRDN and 1 (2.2%) individual in the cardiomyopathy-associated gene DTNA. In addition, 18 structural variants (SVs) were identified in 15 out of the 45 individuals. Two SVs with likely functional impairment were found in the coding regions of PDSS2 and TRPM4 in 2 SUD cases (4.4%). Both were identified as heterozygous deletions, which were confirmed by multiplex ligation-dependent probe amplification. In conclusion, our findings support that SVs could contribute to the pathology of the sudden death event in some of the cases and therefore should be investigated on a routine basis in suspected SUD cases.

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