Whole-exome sequencing to identify causative variants in juvenile sudden cardiac death

Abstract

Background: Juvenile sudden cardiac death (SCD) remains unexplained in approximately 40% of cases, leading to a significant emotional burden for the victims' families and society. Comprehensive investigations are essential to uncover its elusive causes and enable cascade family screening. This study aimed to enhance the identification of likely causative variants in juvenile SCD cases (age ≤ 50 years), particularly when autopsy findings are inconclusive.

Results: Autopsy revealed diagnostic structural abnormalities in 46%, non-diagnostic findings in 23%, and structurally normal hearts in 31% of cases. Whole-exome sequencing (WES), refined through a customized virtual gene panel was used to identify variants. These variants were then evaluated using a multidisciplinary approach and a structured variant prioritization scheme. Our extended approach identified likely causative variants in 69% of cases, outperforming the diagnostic yields of both the cardio panel and standard susceptibility gene analysis (50% and 16%, respectively). The extended cardio panel achieved an 80% diagnostic yield in cases with structurally normal hearts, demonstrating its efficacy in challenging scenarios. Notably, half of the positive cases harboured a single variant, while the remainder had two or more variants.

Conclusion: This study highlights the efficacy of a multidisciplinary approach employing WES and a tailored virtual gene panel to elucidate the aetiology of juvenile SCD. The findings support the expansion of genetic testing using tailored gene panels and prioritization schemes as part of routine autopsy evaluations to improve the identification of causative variants and potentially facilitate early diagnosis in first-degree relatives.

Keywords: Arrhythmia; Cardiomyopathy; Genetic; Molecular autopsy; NGS; Sudden cardiac death.

Fig. 1

Added diagnostic value of the extended cardio panel. The variant detection rate (%) found using different virtual panels in all autopsy cases: core genes 16%, cardio panel 50%, extended cardio panel 69%. “Core genes” represent the 4 main susceptibility genes, “Cardio panel” includes the 174 genes from the TruSight Cardio Panel (Illumina, San Diego, California, USA) and the “extended panel” includes the 1304 genes selected in this study

Fig. 2

Variants diagnostic detection rate (%) in each autopsy group. The cohort of “SCD with diagnostic structural abnormalities” (A) (macroscopic and/or histopathological alterations fell within the diagnostic criteria for a specific cardiomyopathy) shows a detection rate of 14% (2/14) with the major susceptibility genes (core genes), 43% (6/14) with the cardio panel and 57% (8/14) with the extended cardio panel; the core genes have a detection rate of 0% in the group of “SCD with non-diagnostic autopsy findings” (B) (macroscopic and/or histopathological alterations were subtler) (0/8) and of 30% in the group of “SCD with structurally normal heart (SAD)” (3/10); the increase in the detection rate of likely causative variants ranges from 63% (5/8) with the cardio panel to 75% (6/8) with the extended panel for “SCD cases with inconclusive autopsy findings” (C) and from 60% (6/10) to 80% (8/10) for the SAD group

Fig. 3

Cardiomyopathy versus channelopathy genes in different autopsy groups. Probable causative variants in genes associated with cardiomyopathy (orange) are observed more frequently in cases of SCD with diagnostic structural abnormalities (50%) (A) and with non-diagnostic autopsy findings (50%) (B), compared to those with structurally normal hearts (SAD) (25%) (C). Bars are marked with the same symbol when represent the same subject; genes marked with an asterisk present (P/LP) variant

Fig. 4

Diagnostic yield percentages across age groups. Waffle charts depicting diagnostic yield percentages for three age groups: 20–29 years (58%), 30–39 years (67%), and 40–50 years (71%). Each square represents 1% of the total sample. Despite apparent differences, statistical analysis revealed no significant variation in diagnostic yield across age groups (p = 1 for each age class)