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 reanalyzed 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.Results:We confirmed a major contribution of likely pathogenic variants in FLT4 (VEGFR3 [vascular endothelial growth factor receptor 3]; n=14) and NOTCH1 (n=10) and identified 1 to 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 3 emerging congenital heart disease/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=3.3×10⁻¹⁶), with VEGFR2 (vascular endothelial growth factor receptor 2; KDR) and NOTCH1 (neurogenic locus notch homolog protein 1) representing central nodes. Variants associated with arrhythmias/sudden death and 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 congenital heart disease/TOF gene and for VEGF (vascular endothelial growth factor) 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.

中文翻译：

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临床遗传风险变异为法洛四联症的功能蛋白相互作用网络提供信息


背景：法洛四联症（TOF）是新生儿最常见的紫绀性心脏缺陷，有证据表明多种遗传因素有关。识别临床相关的变异对于了解患者特定疾病的易感性和结果至关重要，并有助于描绘病理机制。方法：使用临床驱动的策略，我们使用 TOF 重新分析了 811 个先证者的外显子组测序数据，以识别罕见的丢失 -结果：我们证实了FLT4 （VEGFR3 [血管内皮生长因子受体 3]；n=14）和NOTCH1 (n=10) 中可能的致病性变异的主要贡献鉴定了 21 个其他基因中每个基因的 1 至 3 个变体，包括ATRX 、 DLL4 、 EP300 、 GATA6 、 JAG1 、 NF1 、 PIK3CA 、 RAF1 、 RASA1 、 SMAD2和TBX1 。此外，多种功能丧失变异为 3 个新出现的先天性心脏病/TOF 候选基因提供了支持： KDR (n=4)、 IQGAP1 (n=3) 和GDF1 (n=8)。总共，在 63 名先证者 (7.8%) 中发现了这些变异。在STRING蛋白相互作用富集分析中使用26个复合基因揭示了一个生物学相关网络（ P = 3.3×10 ^-16 ），其中VEGFR2（血管内皮生长因子受体2； KDR ）和NOTCH1（神经源性位点Notch同源蛋白1）代表中心节点。与心律失常/猝死和心力衰竭相关的变异表明可能影响长期结果的因素。结论：结果与TOF精准医疗相关。他们表明全基因组测序具有相当大的临床产量，并进一步证明KDR (VEGFR2) 作为先天性心脏病/TOF 基因，以及 VEGF（血管内皮生长因子）和 Notch 信号传导作为人类疾病的机制。利用单基因缺陷的遗传异质性可以为发病机制提供信息，并有助于优先考虑 TOF 的新候选基因。