Signal-to-Noise Analysis Can Inform the Likelihood That Incidentally Identified Variants in Sarcomeric Genes Are Associated with Pediatric Cardiomyopathy

Figures

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  Figure 1. (A), Schematic of the study methodology. (B), Pie chart of all subjects undergoing ES testing divided into individuals with no HCM gene-associated variant (variant-negative; grey) and individuals who hosted a variant of uncertain significance (VUS; white) or likely pathogenic/pathogenic variants (LP/P, red) according to laboratory interpretation at the time of reporting. (C), Pie chart of ES cohort demonstrating variant-positive individuals with a single variant (white) and those with two or more variants (blue).

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  Figure 2. (A), Bar graph comparing total, radical, and missense variant frequency of HCM-associated variants. (B), Bar graph comparing variant frequency across genes. Comparisons made across a control cohort (gnomAD, white), a cohort of ES referrals (blue), and a cohort of individuals with clinical HCM (green). Error bars denote 95% CI. *, p < 0.05.

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  Figure 3. (A), Bar graph demonstrating the gene-level signal-to-noise ratios for each HCM-associated gene for the HCM case cohort compared with the gnomAD cohort. (B), Bar graph demonstrating the signal-to-noise ratios for each HCM-associated gene for the ES cohort compared with the gnomAD cohort. Error bars denote 95% CI.

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  Figure 4. (A), Amino acid-level signal-to-noise analysis of MYH7 variants for both HCM cases (red) and ES-identified variants (blue), compared with variants identified in the gnomAD cohort. (B), Amino acid-level signal-to-noise analysis of MYBPC3 variants for both HCM cases (red) and ES-identified variants (blue), compared with variants identified in the gnomAD cohort. Functional domains of MYH7 and MYBPC3 are depicted. N, N-terminal domain; Cx, immunoglobulin-like domain; FNx, fibronectin domain; highlighted yellow regions, actin binding sites.

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  Figure 5. (A), Bar graph demonstrating proportion of pathogenic (P), likely pathogenic (LP), and variants of uncertain significance (VUS) using American College of Medical Genetics and Genomics (ACMG) criteria before and after re-assignment with signal-to-noise (S:N). (B), Exome sequencing (ES) cohort was assigned pathogenicity based on 2015 ACMG criteria. A retrospective clinical analysis was performed on those patients seen at Texas Children’s Hospital (TCH) following exclusion of subjects with structural heart disease, mitochondrial disease, or chromosomal abnormalities, or those without echocardiogram. (C), Bar graph showing the percentage of individuals with cardiomyopathy (CM) or first-degree family history (FHx) of cardiomyopathy out of TCH cohort probands hosting VUSs or LP/P variants. (D), Bar graph highlighting the percentage of individuals hosting LP/P variants out of TCH cohort probands with a negative clinical evaluation or cardiomyopathy or first-degree family history of cardiomyopathy. ***, p < 0.001.