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

Genet Med. 2021 Jan;23(1):103-110. doi: 10.1038/s41436-020-00939-4. Epub 2020 Aug 21.


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.

Keywords: HEY2; cardiovascular defects; congenital heart defect; thoracic aortic aneurysm.

Publication types

  • Meta-Analysis

MeSH terms

  • Aortic Aneurysm, Thoracic* / genetics
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Genetic Predisposition to Disease
  • Germ Cells
  • Heart Defects, Congenital* / genetics
  • Humans
  • Pedigree
  • Repressor Proteins


  • Basic Helix-Loop-Helix Transcription Factors
  • HEY2 protein, human
  • Repressor Proteins