Genetics and genomics of congenital heart disease and associated neurodevelopmental abnormalities

 描述(申请人提供)：先天性心脏病(CHD)是最常见的可存活的出生缺陷，影响全球所有活产婴儿的0.7%。CHD的治疗取得了长足的进步，目前成人CHD患者比儿童多，但许多复杂的CHD患者有长期的发病率，经常表现为神经发育异常(NDA)。尽管遗传因素被认为起了一定的作用，但对CHD的发病机制却知之甚少。基因组技术的巨大进步现在使得系统地识别对疾病发病机制有非常大影响的特定基因和途径成为可能。作为PCGC的一部分，我们对从PCGC研究中招募的9000多名患者中挑选的1300名亲子三人进行了全外显子组测序。突出的发现是，发生在心脏高表达基因的从头突变至少占所研究CHD病例的8%，并且不成比例地发生在被归类为左室流出道梗阻的CHD患者以及CHD和NDA患者中。在CHD去新生突变的基因中，涉及染色质修饰的基因突变尤其是破坏性突变明显增多，这些突变强烈倾向于CHD合并NDA的病例。此外，非常出人意料的是，我们发现在冠心病和自闭症中，具有破坏性突变的基因有非常显著的重叠。我们认为，参与染色质调节的基因对心脏和神经发育都是剂量敏感的，这些基因的突变可能导致CHD和NDA。通过对10,000例PCGC患者的染色质修饰组中的所有基因进行测序，利用MIPS(分子反转探针测序)进行快速、廉价的靶向测序，我们将识别这一途径中与CHD有关的基因，并确定它们与NDA的特定关系。由于上一个资金周期使我们能够表明CHD具有高度的基因异质性，我们还将继续使用成本效益高的外显子组测序来识别更多的基因，在这些基因中，去新生突变对疾病风险有很大影响。为了确定染色质修饰物突变导致的NDA谱，我们将从现有的PCGC队列中识别该基因集有无突变的患者，并进行神经发育测试。最后，我们将前瞻性地招募一岁以下的患者，测试染色质修饰基因突变，并跟踪他们的神经发育结果。综上所述，我们希望这些研究能够确定一组易于测试的基因，这些基因可以快速、廉价地进行评估，以确定具有增加ND异常风险的CHD患者。

 DESCRIPTION (provided by applicant): Congenital heart disease (CHD) is the most common survivable birth defect, affecting 0.7% of all liveborn infants worldwide. Management of CHD has made great strides, so that there are now more living adults with CHD than children, but many patients with complex CHD have long-term morbidity frequently manifesting as neurodevelopmental abnormalities (NDA). The causative mechanisms of CHD have been poorly understood although genetic factors are strongly believed to play a role. Dramatic advances in genomic technologies now allow systematic identification of specific genes and pathways that have very large effects on disease pathogenesis. As part of the PCGC, we have performed whole-exome sequencing on 1,300 parent-offspring trios selected from over 9,000 patients recruited into the PCGC study. The salient findings are that de novo mutations occurring in genes that are highly expressed in the heart account for at least 8% of the CHD cases studied, and disproportionately occur in patients with CHD classified as left ventricular outflow obstruction, and in patients with CHD and NDA. Among the genes with de-novo mutations in CHD there is a marked enrichment of mutations, particularly damaging mutations, in genes involved in chromatin modification, and these mutations are strongly biased toward CHD cases with NDA. Moreover, and very unexpectedly, we find highly significant overlap of genes with damaging mutations in CHD and in autism. We propose that genes involved in chromatin regulation are dosage sensitive for both heart and neurodevelopment, and that mutations in these genes can result in both CHD and NDA. By sequencing all genes in the chromatin modification set in 10,000 PCGC cases using rapid, inexpensive targeted sequencing via MIPS (molecular inversion probe sequencing) we will identify genes in this pathway that contribute to CHD and determine their specific relationship to NDA. Since the last funding cycle has enabled us to show that CHD has high locus heterogeneity, we will also continue to use cost-effective exome sequencing to identify additional genes in which de-novo mutations confer large effects on disease risk. In order to determine the spectrum of NDA resulting from chromatin modifier mutations, we will identify patients from the existing PCGC cohort with and without mutation in this gene set and perform neurodevelopmental testing. Finally, we will prospectively recruit patients under one year of age, test for chromatin modifier mutations, and follow their neurodevelopmental outcome. In summary, we expect these studies to identify an easily testable set of genes that can be evaluated rapidly and inexpensively to identify CHD patients at increased risk for ND abnormalities.