{Reference Type}: Journal Article
{Title}: Germline variants in HEY2 functional domains lead to congenital heart defects and thoracic aortic aneurysms.
{Author}: van Walree ES;Dombrowsky G;Jansen IE;Mirkov MU;Zwart R;Ilgun A;Guo D;Clur SB;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;
{Journal}: Genet Med
{Volume}: 23
{Issue}: 1
{Year}: 01 2021
{Factor}: 8.864
{DOI}: 10.1038/s41436-020-00939-4
{Abstract}: 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.