Genetic Testing for Inherited Cardiac Arrhythmias: Current State-of-the-Art and Future Avenues

Figures

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  Figure 1:. Relationship between genotype and phenotype. A rare genetic variant with a large effect (genotype) leads to a phenotype with varying degrees of penetrance (fading colors) and expressivity (different colors). This relationship is affected by many other factors and is fundamentally predicated on the accuracy of sequencing and interpretation of the genetic variant and identification of clinical manifestations.

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  Figure 2:. Criteria proposed by the ACMG for the interpretation of sequence variants. Depicted are specific variant characteristics, the categorization of which leads to the determination of pathogenic or likely pathogenic status. Variants that do not fulfill these criteria are considered to be of unknown significance or benign. For full details, see Richards et al.6

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  Figure 3:. Different consequences of genetic sequence variation. Displayed in each panel is the wild-type sequence with specific nucleotide variation and the subsequent amino acid consequence. A: Missense: a single nucleotide point variant (G to C) changes the amino acid from arginine to threonine. There is no change in the downstream reading frame or amino acids. B: Nonsense: another single-point variant (T to G) changes tyrosine to a premature stop codon and protein truncation. C: Splice variant: the nucleotide coding sequence and amino acid sequence within the exon are normal, but the first nucleotide in the intron has changed (G to A). Spliceosomes depend on the nucleotide sequence at exon–intron boundaries and, if variation in the nucleotide sequence occurs in the canonical splice sites at the exon–intron boundaries, such variation can lead to abnormal splicing and either exonic skipping or intronic inclusion. D: Frameshift insertion: a single nucleotide (A) is inserted (dashed arrow) and hence alters the downstream reading frame and typically leads to a stop codon and premature truncation, in this case after only one further amino acid residue. E: Inframe deletion: three nucleotides…

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  Figure 4:. Topology of the genes KCNQ1 and RyR2. The upper panel depicts KCNQ1 associated with LQTS1. The cytoplasmic loops are depicted as the red dashed line and the C-terminal is depicted as the blue dashed line. The positions of amino acid residues 300 in the pore helix and 518 in the C-terminal are shown. The lower panel depicts RyR2 associated with CPVT. The four canonical domains where the majority of disease-associated variants are located are depicted as a red dashed line, along with the first and last amino acid residues depicted numerically. See the text for further details.