Background - Tetralogy 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 - Using a clinically-driven strategy, we re-analyzed exome sequencing data from 811 probands with TOF, to identify rare loss-of-function and other likely pathogenic variants in genes associated with congenital heart disease (CHD). Results - We confirmed a major contribution of likely pathogenic variants in FLT4 (VEGFR3; n=14) and NOTCH1 (n=10), and identified 1-3 variants in each of 21 other genes, including ATRX , DLL4 , EP300 , GATA6 , JAG1 , NF1 , PIK3CA , RAF1 , RASA1 , SMAD2 , and TBX1 . In addition, multiple loss-of-function variants provided support for three emerging CHD/TOF candidate genes: KDR (n=4), IQGAP1 (n=3), and GDF1 (n=8). In total, these variants were identified in 63 probands (7.8%). 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. Conclusions - The results are relevant to precision medicine for TOF. They suggest considerable clinical yield from genome-wide sequencing, with further evidence for KDR (VEGFR2) as a CHD/TOF gene, and for vascular endothelial growth factor (VEGF) and Notch signaling as mechanisms in human disease. Harnessing the genetic heterogeneity of single gene defects could inform etiopathogenesis and help prioritize novel candidate genes for TOF.
No abstract
Background: Tetralogy 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 Results: We 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. Conclusions: The 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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