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BackgroundTetralogy of Fallot (TOF), the most common cyanotic heart defect in newborns, has evidence of multiple genetic contributing factors. Identifying variants that are clinically relevant is essential to understand patient-specific disease susceptibility and outcomes, and could contribute to delineating pathomechanisms. Methods and ResultsWe used a clinically-driven strategy and current guidelines to re-analyze exome sequencing data from 811 probands with TOF, focused on identifying rare loss-of-function and other likely pathogenic variants in congenital heart disease (CHD) genes. In addition to confirming a major contribution of likely pathogenic variants in FLT4 (VEGFR3; n=14) and NOTCH1 (n=11), we identified 1-3 such variants in each of 21 other CHD genes, including ATRX, DLL4, EP300, GATA6, JAG1, NF1, PIK3CA, RAF1, RASA1, SMAD2, and TBX1. There were also three emerging CHD/TOF candidate genes with multiple loss-of-function variants in this cohort: KDR (n=4), IQGAP1 (n=3), and GDF1 (n=8). In total, these variants were identified in 64 probands (7.9%). Using the 26 composite genes in a STRING protein interaction enrichment analysis revealed a biologically relevant network (p-value 3.3e-16), with VEGFR2 (KDR) and NOTCH1 representing central nodes. Variants associated with arrhythmias/sudden death and/or heart failure indicated factors that could influence long-term outcomes. ConclusionsThe results are relevant to precision medicine for TOF. They suggest considerable clinical yield from genome-wide sequencing, and further evidence for KDR as a CHD/TOF gene and VEGF and Notch signaling as mechanisms in human disease. Harnessing genetic heterogeneity of single gene defects could inform etiopathogenesis and help prioritize novel candidate genes for TOF.

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