Purpose This study investigated the diagnostic utility of nontargeted genomic testing in patients with pediatric heart disease. Methods We analyzed genome sequencing data of 111 families with cardiac lesions for rare, disease-associated variation. Results In 14 families (12.6%), we identified causative variants: seven were de novo (ANKRD11, KMT2D, NR2F2, POGZ, PTPN11, PURA, SALL1) and six were inherited from parents with no or subclinical heart phenotypes (FLT4, DNAH9, MYH11, NEXMIF, NIPBL, PTPN11). Outcome of the testing was associated with the presence of extracardiac features (p = 0.02), but not a positive family history for cardiac lesions (p = 0.67). We also report novel plausible gene–disease associations for tetralogy of Fallot/pulmonary stenosis (CDC42BPA, FGD5), hypoplastic left or right heart (SMARCC1, TLN2, TRPM4, VASP), congenitally corrected transposition of the great arteries (UBXN10), and early-onset cardiomyopathy (TPCN1). The identified candidate genes have critical functions in heart development, such as angiogenesis, mechanotransduction, regulation of heart size, chromatin remodeling, or ciliogenesis. Conclusion This data set demonstrates the diagnostic and scientific value of genome sequencing in pediatric heart disease, anticipating its role as a first-tier diagnostic test. The genetic heterogeneity will necessitate large-scale genomic initiatives for delineating novel gene–disease associations.

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Whole-genome sequencing and whole-exome sequencing have proven valuable for diagnosing inherited diseases, particularly in children. However, usage of sequencing data as a pharmacogenetic screening tool to ensure medication safety and effectiveness remains to be explored. Sixty-seven variants in 19 genes with known effects on drug response were compared between genome sequencing and targeted genotyping data for coverage and concordance in 98 pediatric patients. We used targeted genotyping data as a benchmark to assess accuracy of variant calling, and to identify copy number variations of the CYP2D6 gene. We then predicted clinical impact of these variants on drug therapy. We find genotype concordance across those panels to be > 97%. Concordance of CYP2D6 predicted phenotype between estimates of whole-genome sequencing and targeted genotyping panel were 90%; a result from a lower coverage depth or variant calling difficulties in our whole-genome sequencing data when copy number variation and/or the CYP2D6*4 haplotype were present. Importantly, 95 children had at least one clinically actionable pharmacogenetic variant. Diagnostic genomic sequencing data can be used for pre-emptive pharmacogenetic screening. However, concordance between genome-wide sequencing and target genotyping needs to be characterized for each of the pharmacologically important genes.