CGEn (M.S.R.), The Hospital for Sick Children, Toronto, ON, Canada.
Center for Applied Genomics (M.S.R., G.P., O.H., W.W.L.S., T.N., C.R.M., B.T., S.W.S.), The Hospital for Sick Children, Toronto, ON, Canada.
Circ Genom Precis Med. 2021 Aug;14(4):e003410. doi: 10.1161/CIRCGEN.121.003410. Epub 2021 Jul 30.
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.
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.
We confirmed a major contribution of likely pathogenic variants in (VEGFR3 [vascular endothelial growth factor receptor 3]; n=14) and (n=10) and identified 1 to 3 variants in each of 21 other genes, including , , , , , , , , , , and . In addition, multiple loss-of-function variants provided support for 3 emerging congenital heart disease/TOF candidate genes: (n=4), (n=3), and (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 (=3.3×10), with VEGFR2 (vascular endothelial growth factor receptor 2; ) 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.
The results are relevant to precision medicine for TOF. They suggest considerable clinical yield from genome-wide sequencing, with further evidence for (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.
法洛四联症（TOF）是新生儿中最常见的发绀性心脏缺陷，有证据表明其存在多种遗传致病因素。确定具有临床相关性的变异对于了解患者特定的疾病易感性和结局至关重要，并且有助于阐明发病机制。
我们使用临床驱动的策略，重新分析了 811 名 TOF 先证者的外显子组测序数据，以鉴定与先天性心脏病相关基因中的罕见功能丧失和其他可能的致病性变异。
我们证实了 （血管内皮生长因子受体 3[VEGFR3]；n=14）和 （n=10）中的可能致病性变异对 TOF 有重要贡献，并在 21 个其他基因中每个基因鉴定出 1 到 3 个变异，包括 （n=4）、 （n=5）、 （n=3）、 （n=4）、 （n=3）、 （n=5）、 （n=4）、 （n=3）、 （n=3）、 （n=3）和 （n=8）。总共，这些变异在 63 名先证者（7.8%）中被发现。在 STRING 蛋白质相互作用富集分析中，使用这 26 个复合基因揭示了一个具有生物学相关性的网络（=3.3×10），其中 VEGFR2（血管内皮生长因子受体 2；）和 NOTCH1（神经源性巢蛋白 1）是中心节点。与心律失常/猝死和心力衰竭相关的变异表明了可能影响长期结局的因素。
这些结果与 TOF 的精准医学相关。它们表明全基因组测序具有相当大的临床收益，进一步证明 （VEGFR2）是先天性心脏病/TOF 基因，并且 VEGF（血管内皮生长因子）和 Notch 信号作为人类疾病的机制。利用单个基因缺陷的遗传异质性可以为发病机制提供信息，并有助于为 TOF 确定新的候选基因。
