Germline variants in HEY2 functional domains lead to congenital heart defects and thoracic aortic aneurysms
van Walree ES, Dombrowsky G, Jansen IE, Mirkov MU, Zwart R, Ilgun A, Guo D, Clur SAB, Amin AS, Savage JE, van der Wal AC, Waisfisz Q, Maugeri A, Wilsdon A, Bu’Lock FA, Hurles ME, Dittrich S, Berger F, Audain Martinez E, Christoffels VM, Hitz MP, Milewicz DM, Posthuma D, Meijers-Heijboer H, Postma AV, Mathijssen IB (2020)
Publication Type: Journal article
Publication year: 2020
Journal
DOI: 10.1038/s41436-020-00939-4
Abstract
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.
Authors with CRIS profile
Involved external institutions
University of Amsterdam
Netherlands (NL)
Universitätsklinikum Schleswig-Holstein (UKSH)
Germany (DE)
University of Leicester
United Kingdom (GB)
Amsterdam University Medical Centers (Amsterdam UMC) / Amsterdam Universitair Medische Centra
Netherlands (NL)
Deutsches Herzzentrum Berlin
Germany (DE)
Vrije Universiteit Amsterdam (VU) / University Amsterdam
Netherlands (NL)
University of Nottingham
United Kingdom (GB)
University of Texas Health Science Center at Houston (UTHealth)
United States (USA) (US)
Netherlands (NL)
Universitätsklinikum Schleswig-Holstein (UKSH)
Germany (DE)
University of Leicester
United Kingdom (GB)
Amsterdam University Medical Centers (Amsterdam UMC) / Amsterdam Universitair Medische Centra
Netherlands (NL)
Deutsches Herzzentrum Berlin
Germany (DE)
Vrije Universiteit Amsterdam (VU) / University Amsterdam
Netherlands (NL)
University of Nottingham
United Kingdom (GB)
University of Texas Health Science Center at Houston (UTHealth)
United States (USA) (US)
How to cite
APA:
van Walree, E.S., Dombrowsky, G., Jansen, I.E., Mirkov, M.U., Zwart, R., Ilgun, A.,... Mathijssen, I.B. (2020). Germline variants in HEY2 functional domains lead to congenital heart defects and thoracic aortic aneurysms. Genetics in Medicine. https://doi.org/10.1038/s41436-020-00939-4
MLA:
van Walree, Eva S., et al. "Germline variants in HEY2 functional domains lead to congenital heart defects and thoracic aortic aneurysms." Genetics in Medicine (2020).
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