Germline variants in HEY2 functional domains lead to congenital heart defects and thoracic aortic aneurysms.,Genetics in Medicine

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Germline variants in HEY2 functional domains lead to congenital heart defects and thoracic aortic aneurysms.
Genetics in Medicine ( IF 8.8 ) Pub Date : 2020-08-21 , DOI: 10.1038/s41436-020-00939-4
Eva S van Walree _{1,

2} , Gregor Dombrowsky ₃ , Iris E Jansen _{2,

4} , Maša Umićević Mirkov ₂ , Rob Zwart ₅ , Aho Ilgun ₅ , Dongchuan Guo ₆ , Sally-Ann B Clur ₇ , Ahmed S Amin ₈ , Jeanne E Savage ₂ , Allard C van der Wal ₉ , Quinten Waisfisz ₁₀ , Alessandra Maugeri ₁₀ , Anna Wilsdon ₁₁ , Frances A Bu'Lock ₁₂ , Matthew E Hurles ₁₃ , Sven Dittrich ₁₄ , Felix Berger _{15,

16} , Enrique Audain Martinez ₃ , Vincent M Christoffels ₅ , Marc-Philip Hitz ₃ , Dianna M Milewicz ₆ , Daniëlle Posthuma ₂ , Hanne Meijers-Heijboer _{1,

10} , Alex V Postma _{1,

5} , Inge B Mathijssen ₁

Affiliation

Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University, Amsterdam, The Netherlands.
Department of Congenital Heart Disease and Pediatric Cardiology, Universitätsklinikum Schleswig-Holstein Kiel, Kiel, Germany.
Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands.
Department of Medical Biology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.
Department of Pediatric Cardiology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
Department of Clinical and Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
Department of Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit Medisch Centrum, Amsterdam, The Netherlands.
School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham, United Kingdom.
East Midlands Congenital Heart Centre and University of Leicester, Glenfield Hospital, Leicester, United Kingdom.
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom.
Department of Pediatric Cardiology, University of Erlangen-Nürnberg, Erlangen, Germany.
German Heart Center Berlin, Department of Congenital Heart Disease, Pediatric Cardiology, Berlin, Germany.
DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany.

Purpose

In this study we aimed to establish the genetic cause of a myriad of cardiovascular defects prevalent in individuals from a genetically isolated population, who were found to share a common ancestor in 1728.

Methods

Trio genome sequencing was carried out in an index patient with critical congenital heart disease (CHD); family members had either exome or Sanger sequencing. To confirm enrichment, we performed a gene-based association test and meta-analysis in two independent validation cohorts: one with 2685 CHD cases versus 4370 . These controls were also ancestry-matched (same as FTAA controls), and the other with 326 cases with familial thoracic aortic aneurysms (FTAA) and dissections versus 570 ancestry-matched controls. Functional consequences of identified variants were evaluated using expression studies.

Results

We identified a loss-of-function variant in the Notch target transcription factor-encoding gene HEY2. The homozygous state (n = 3) causes life-threatening congenital heart defects, while 80% of heterozygous carriers (n = 20) had cardiovascular defects, mainly CHD and FTAA of the ascending aorta. We confirm enrichment of rare risk variants in HEY2 functional domains after meta-analysis (MetaSKAT p = 0.018). Furthermore, we show that several identified variants lead to dysregulation of repression by HEY2.

Conclusion

A homozygous germline loss-of-function variant in HEY2 leads to critical CHD. The majority of heterozygotes show a myriad of cardiovascular defects.

中文翻译：

HEY2 功能域中的种系变异导致先天性心脏缺陷和胸主动脉瘤。

目的

在这项研究中，我们旨在确定遗传隔离人群中普遍存在的无数心血管缺陷的遗传原因，这些人群在 1728 年被发现具有共同的祖先。

方法

Trio 基因组测序是在一名患有严重先天性心脏病 (CHD) 的索引患者中进行的；家庭成员有外显子组或 Sanger 测序。为了确认富集，我们在两个独立的验证队列中进行了基于基因的关联测试和荟萃分析：一个有 2685 个 CHD 病例，一个有 4370 个。这些对照也是血统匹配的（与 FTAA 对照相同），另一组有 326 例家族性胸主动脉瘤 (FTAA) 和夹层病例与 570 例血统匹配的对照。使用表达研究评估已识别变体的功能后果。

结果

我们在 Notch 靶转录因子编码基因HEY2中发现了一个功能缺失变体。纯合状态（n = 3）导致危及生命的先天性心脏缺陷，而80％的杂合携带者（n = 20）有心血管缺陷，主要是升主动脉的CHD和FTAA。我们在荟萃分析后证实了HEY2功能域中罕见风险变异的富集（MetaSKAT p = 0.018）。此外，我们发现几个已识别的变体导致 HEY2 抑制的失调。