Figure 2
From: Toward an effective exome-based genetic testing strategy in pediatric dilated cardiomyopathy
Our proposed stepwise diagnostic approach for analyzing pediatric DCM patients and the resulting internal and potential yields. Step 1. Analysis of a limited selection of 60 genes, encoding mostly structural components of cardiomyocytes. Step 2. CNV analysis, including homozygosity analysis. Step 3. Reanalysis of the data by filtering for variants in a comprehensive virtual gene panel, based on the HPO term “cardiomyopathy.” Step 4. Adding more HPO terms for filtering in those patients presenting with additional cardiac and/or noncardiac features. In the group without a diagnosis, 43% (31/72 families) agreed to undergo ES and CNV analysis. We reasoned that the group of 16 patients (from 13 families, Supplementary Table S1) with a known genetic diagnosis, to whom we did not offer ES/CNV analysis, would not differ much from the group that was eligible for ES/CNV analysis (e.g., no bias in severity of DCM or number of familial cases). Therefore, the same percentage of inclusions should also be applicable to this “not offered ES/CNV analysis” group. Eleven of these 13 families would have been identified by our approach if ES/CNV analysis had been performed as the first-tier test. The potential yield would therefore be the sum of the internal yield (15/31 families) plus the 0.43 proportion of the excluded patients who already had a genetic diagnosis (15+(11*0.43))/(31+(13*0.43)), which is 53.9%. CM, cardiomyopathy; CNV, copy-number variation; DCM, dilated cardiomyopathy; ES, exome sequencing; HPO, Human Phenotype Ontology; SNP, single-nucleotide polymorphism; VUS, variant of uncertain clinical significance; WES, whole-exome sequencing.
