Functional genomics and gene-environment interaction highlight the complexity of congenital heart disease caused by Notch pathway variants
Functional genomics and gene-environment interaction highlight the complexity of congenital heart disease caused by Notch pathway variants
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DOI：
10.1093/hmg/ddz270
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发表时间：
2020-02-15
影响因子：
3.5
通讯作者：
Dunwoodie, Sally L.
中科院分区：
文献类型：
--
作者：
Chapman, Gavin;Moreau, Julie L. M.;Dunwoodie, Sally L.
先天性心脏病(CHD)是最常见的出生缺陷，并伴随着巨大的死亡率和发病率。外显子组和基因组测序的应用极大地提高了CHD的基因诊断率，但大多数病例的病因尚不清楚。很明显，遗传因素以及环境因素在冠心病的病因中起着重要作用。在这里，我们讨论与Notch信号通路有关的这两个方面的因果关系。在我们的CHD队列中，核心Notch途径基因的变异占致病基因的20%，这一比例没有随着更广泛的Notch途径及其调节因子的基因的加入而增加。这一点在病例对照负担分析中得到了加强，其中在冠心病患者中Notch途径基因的变异是丰富的。这种浓缩是由于NOTCH1的变异造成的。对培养细胞中一些新的错义NOTCH1和DLL4变体的功能分析表明，信号活性降低，允许变体重新分类。虽然已知DLL4功能缺失变异可导致亚当斯-奥利弗综合征，但这是首次报道DLL4等位基因低态是导致单纯性CHD的原因。最后，我们在小鼠胚胎中证明了Notch1杂合子和低氧或抗心律失常药物诱导的妊娠低氧之间的基因-环境相互作用，从而导致心脏缺陷发生率增加。这意味着暴露于环境侮辱，如低氧，可以解释携带Notch途径变异的家庭中观察到的CHD的不同表达和外显率。
Congenital heart disease (CHD) is the most common birth defect and brings with it significant mortality and morbidity. The application of exome and genome sequencing has greatly improved the rate of genetic diagnosis for CHD but the cause in the majority of cases remains uncertain. It is clear that genetics, as well as environmental influences, play roles in the aetiology of CHD. Here we address both these aspects of causation with respect to the Notch signalling pathway. In our CHD cohort, variants in core Notch pathway genes account for 20% of those that cause disease, a rate that did not increase with the inclusion of genes of the broader Notch pathway and its regulators. This is reinforced by case-control burden analysis where variants in Notch pathway genes are enriched in CHD patients. This enrichment is due to variation in NOTCH1. Functional analysis of some novel missense NOTCH1 and DLL4 variants in cultured cells demonstrate reduced signalling activity, allowing variant reclassification. Although loss-of-function variants in DLL4 are known to cause Adams-Oliver syndrome, this is the first report of a hypomorphic DLL4 allele as a cause of isolated CHD. Finally, we demonstrate a gene-environment interaction in mouse embryos between Notch1 heterozygosity and low oxygen- or anti-arrhythmic drug-induced gestational hypoxia, resulting in an increased incidence of heart defects. This implies that exposure to environmental insults such as hypoxia could explain variable expressivity and penetrance of observed CHD in families carrying Notch pathway variants.