The burden of splice-disrupting variants in inherited heart disease and unexplained sudden cardiac death

Figures

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  Fig. 1. The proportion of participants with an in silico-predicted splice-disrupting variant. Total participant counts within each disease group are shown in the boxes above each bar plot. The overall average of participants with an in silico-predicted splice-disrupting variant (10.3%) is highlighted by the red dotted line. HCM hypertrophic cardiomyopathy, SUD sudden unexplained death, DCM dilated cardiomyopathy, BrS Brugada syndrome, LQTS long QT syndrome, ACM arrhythmogenic cardiomyopathy, and CPVT catecholaminergic polymorphic ventricular tachycardia.

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  Fig. 2. The percentage of unique in silico-predicted splice-disrupting variants in each gene. Percentage of unique in silico-predicted splice-disrupting variants found in a list of 32 genes prioritised based on phenotypically concordant genes established by the ClinGen Curation Expert groups for hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogenic cardiomyopathy, long QT syndrome, Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia.

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  Fig. 3. Location of unique in silico-predicted splice-disrupting variants in the essential splice site region. The positions of the essential GT/AG dinucleotides are shown in red. The splice donor site consists of the last three nucleotides of the exon and the first six nucleotides of the intron. The acceptor site consists of the last 20 nucleotides of the intron and the first three nucleotides of the exon. The intervening intron is truncated ‘//’. Three small deletions within the splice site region are not shown.

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  Fig. 4. Classification of in silico-predicted splice-disrupting variants. Variants located in the −3 to +6 region of the donor site or the −20 to +3 region of the acceptor site are classified as ‘Splice site region’ variants. All other intronic variants were labelled as ‘deep intronic region’. Remaining variants in the exons, including missense, nonsense, and synonymous variants, were categorised as ‘exonic region’.