美国西奈山伊坎医学院Bruce D. Gelb课题组取得一项新突破。他们利用基因组分析表明先天性心脏病（CHD）的非编码从头编码变异（DNV）。2020年6月29日出版的《自然-遗传学》杂志发表了这项成果。

为了评估非编码DNV对CHD的贡献，他们比较了749个CHD先证者及其父母的基因组序列与1,611个未受影响的三者的基因组序列。与对照组（n = 4,177; P = 8.7×10-4）相比，非编码DNV转录影响的神经网络预测确定了CHD患者（n = 2,238 DNV）的DNV负荷。

对增强子的独立分析显示，DNV在相关基因中过多（27个基因与预期的3.7个相比，P = 1×10-5）。他们观察到这些基于转录的方法之间存在显著重叠（比值比（OR）= 2.5，95％置信区间（CI）1.1-5.0，P = 5.4×10-3）。CHD DNV改变了所检测的31种增强子中5种的转录水平。

最后，他们在RNA结合蛋白调控位点观察到DNV负荷（OR = 1.13，95％CI 1.1-1.2，P = 8.8×10-5）。他们的发现表明，在CHD中，潜在破坏性调节性非编码DNV的富集程度至少与破坏性编码DNV所观察到的一样高。

据悉，三分之一的CHD患者病因被发现，其中8％的病例归因于DNV。

附：英文原文

Title: Genomic analyses implicate noncoding de novo variants in congenital heart disease

Author: Felix Richter, Sarah U. Morton, Seong Won Kim, Alexander Kitaygorodsky, Lauren K. Wasson, Kathleen M. Chen, Jian Zhou, Hongjian Qi, Nihir Patel, Steven R. DePalma, Michael Parfenov, Jason Homsy, Joshua M. Gorham, Kathryn B. Manheimer, Matthew Velinder, Andrew Farrell, Gabor Marth, Eric E. Schadt, Jonathan R. Kaltman, Jane W. Newburger, Alessandro Giardini, Elizabeth Goldmuntz, Martina Brueckner, Richard Kim, George A. Porter, Daniel Bernstein, Wendy K. Chung, Deepak Srivastava, Martin Tristani-Firouzi, Olga G. Troyanskaya, Diane E. Dickel, Yufeng Shen, Jonathan G. Seidman, Christine E. Seidman, Bruce D. Gelb

Issue&Volume: 2020-06-29

Abstract: A genetic etiology is identified for one-third of patients with congenital heart disease (CHD), with 8% of cases attributable to coding de novo variants (DNVs). To assess the contribution of noncoding DNVs to CHD, we compared genome sequences from 749 CHD probands and their parents with those from 1,611 unaffected trios. Neural network prediction of noncoding DNV transcriptional impact identified a burden of DNVs in individuals with CHD (n=2,238 DNVs) compared to controls (n=4,177; P=8.7×104). Independent analyses of enhancers showed an excess of DNVs in associated genes (27 genes versus 3.7 expected, P=1×105). We observed significant overlap between these transcription-based approaches (odds ratio (OR)=2.5, 95% confidence interval (CI) 1.1–5.0, P=5.4×103). CHD DNVs altered transcription levels in 5 of 31 enhancers assayed. Finally, we observed a DNV burden in RNA-binding-protein regulatory sites (OR=1.13, 95% CI 1.1–1.2, P=8.8×105). Our findings demonstrate an enrichment of potentially disruptive regulatory noncoding DNVs in a fraction of CHD at least as high as that observed for damaging coding DNVs.

DOI: 10.1038/s41588-020-0652-z

Source: https://www.nature.com/articles/s41588-020-0652-z