Germline variants in HEY2 functional domains lead to congenital heart defects and thoracic aortic aneurysms

Eva S. van Walree*, Gregor Dombrowsky, Iris E. Jansen, Maša Umićević Mirkov, Rob Zwart, Aho Ilgun, Dongchuan Guo, Sally-Ann B. Clur, Ahmed S. Amin, Jeanne E. Savage, Allard C. van der Wal, Quinten Waisfisz, Alessandra Maugeri, Anna Wilsdon, Frances A. Bu’Lock, Matthew E. Hurles, Sven Dittrich, Felix Berger, Enrique Audain Martinez, Vincent M. ChristoffelsMarc-Philip Hitz, Dianna M. Milewicz, Daniëlle Posthuma, Hanne Meijers-Heijboer, Alex V. Postma, Inge B. Mathijssen*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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.
Original languageEnglish
Pages (from-to)103-110
Number of pages8
JournalGenetics in Medicine
Issue number1
Early online date2020
Publication statusPublished - Jan 2021

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