Genomic analyses implicate noncoding de novo variants in congenital heart disease.,Nature Genetics

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Genomic analyses implicate noncoding de novo variants in congenital heart disease.
Nature Genetics ( IF 30.8 ) Pub Date : 2020-06-29 , DOI: 10.1038/s41588-020-0652-z
Felix Richter ₁ , Sarah U Morton _{2,

3} , Seong Won Kim ₄ , Alexander Kitaygorodsky ₅ , Lauren K Wasson ₄ , Kathleen M Chen ₆ , Jian Zhou _{6,

7,

8} , Hongjian Qi ₅ , Nihir Patel ₉ , Steven R DePalma ₄ , Michael Parfenov ₄ , Jason Homsy _{4,

10} , Joshua M Gorham ₄ , Kathryn B Manheimer _{1,

11} , Matthew Velinder ₁₂ , Andrew Farrell ₁₂ , Gabor Marth ₁₂ , Eric E Schadt _{9,

11,

13} , Jonathan R Kaltman ₁₄ , Jane W Newburger ₁₅ , Alessandro Giardini ₁₆ , Elizabeth Goldmuntz _{17,

18} , Martina Brueckner ₁₉ , Richard Kim ₂₀ , George A Porter ₂₁ , Daniel Bernstein ₂₂ , Wendy K Chung ₂₃ , Deepak Srivastava ₂₄ , Martin Tristani-Firouzi ₂₅ , Olga G Troyanskaya _{6,

7,

26} , Diane E Dickel ₂₇ , Yufeng Shen ₅ , Jonathan G Seidman ₄ , Christine E Seidman _{4,

28} , Bruce D Gelb _{9,

29,

30}

Affiliation

Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
Division of Newborn Medicine, Boston Children's Hospital, Boston, MA, USA.
Department of Genetics, Harvard Medical School, Boston, MA, USA.
Departments of Systems Biology and Biomedical Informatics, Columbia University, New York, NY, USA.
Flatiron Institute, Simons Foundation, New York, NY, USA.
Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA.
Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Center for External Innovation, Takeda Pharmaceuticals USA, Cambridge, MA, USA.
Sema4, Stamford, CT, USA.
Department of Human Genetics, Utah Center for Genetic Discovery, University of Utah School of Medicine, Salt Lake City, UT, USA.
Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Heart Development and Structural Diseases Branch, Division of Cardiovascular Sciences, NHLBI/NIH, Bethesda, MD, USA.
Boston Children's Hospital, Boston, MA, USA.
Cardiorespiratory Unit, Great Ormond Street Hospital, London, UK.
Division of Cardiology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Departments of Pediatrics and Genetics, Yale University School of Medicine, New Haven, CT, USA.
Children's Hospital Los Angeles, Los Angeles, CA, USA.
Department of Pediatrics, University of Rochester, Rochester, NY, USA.
Department of Pediatrics, Stanford University, Palo Alto, CA, USA.
Departments of Pediatrics and Medicine, Columbia University Medical Center, New York, NY, USA.
Gladstone Institute of Cardiovascular Disease and University of California San Francisco, San Francisco, CA, USA.
Division of Pediatric Cardiology, University of Utah School of Medicine, Salt Lake City, UT, USA.
Department of Computer Science, Princeton University, Princeton, NJ, USA.
Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Lab, Berkeley, CA, USA.
Department of Cardiology, Brigham and Women's Hospital, Boston, MA, USA.
Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

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 × 10⁻⁴). Independent analyses of enhancers showed an excess of DNVs in associated genes (27 genes versus 3.7 expected, P = 1 × 10⁻⁵). 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 × 10⁻³). 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 × 10⁻⁵). 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.

中文翻译：

基因组分析表明先天性心脏病中存在非编码从头变异。

三分之一的先天性心脏病 (CHD) 患者已确定遗传病因，其中 8% 的病例可归因于编码新生变异 (DNV)。为了评估非编码 DNV 对 CHD 的影响，我们将 749 名 CHD 先证者及其父母的基因组序列与 1,611 名未受影响的三人组的基因组序列进行了比较。非编码 DNV 转录影响的神经网络预测发现，与对照组 ( n = 4,177；P = 8.7 × 10 ^-4 ) 相比，CHD 患者 ( n = 2,238 DNV) 的 DNV 负担更大。增强子的独立分析显示相关基因中存在过量的 DNV（27 个基因与预期的 3.7 个基因，P = 1 × 10 ^-5）。我们观察到这些基于转录的方法之间存在显着重叠（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 个增强子中 5 个的转录水平。最后，我们观察到 RNA 结合蛋白调控位点的 DNV 负担（OR = 1.13，95% CI 1.1–1.2，P = 8.8 × 10 ^-5）。我们的研究结果表明，部分 CHD 中潜在破坏性监管非编码 DNV 的富集程度至少与观察到的破坏性编码 DNV 的富集程度相同。

更新日期：2020-06-29

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