%0 Journal Article
%T Germline variants in HEY2 functional domains lead to congenital heart defects and thoracic aortic aneurysms.
%A van Walree ES
%A Dombrowsky G
%A Jansen IE
%A Mirkov MU
%A Zwart R
%A Ilgun A
%A Guo D
%A Clur SB
%A Amin AS
%A Savage JE
%A van der Wal AC
%A Waisfisz Q
%A Maugeri A
%A Wilsdon A
%A Bu'Lock FA
%A Hurles ME
%A Dittrich S
%A Berger F
%A Audain Martinez E
%A Christoffels VM
%A Hitz MP
%A Milewicz DM
%A Posthuma D
%A Meijers-Heijboer H
%A Postma AV
%A Mathijssen IB
%J Genet Med
%V 23
%N 1
%D 01 2021
%M 32820247
%F 8.864
%R 10.1038/s41436-020-00939-4
%X 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.<BR>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.<BR>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.<BR>A homozygous germline loss-of-function variant in HEY2 leads to critical CHD. The majority of heterozygotes show a myriad of cardiovascular defects.