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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.
Details
; Dombrowsky Gregor 2 ; Jansen, Iris E 3 ; Mirkov, Maša Umićević 4 ; Zwart, Rob 5 ; Aho, Ilgun 5 ; Guo Dongchuan 6 ; Clur, Sally-Ann B 7 ; Amin, Ahmed S 8 ; Savage, Jeanne E 4 ; van der Wal Allard C 9 ; Waisfisz Quinten 10 ; Maugeri Alessandra 10 ; Wilsdon, Anna 11 ; Bu’Lock Frances A 12 ; Hurles, Matthew E 13 ; Dittrich Sven 14 ; Berger, Felix 15 ; Audain Martinez Enrique 2 ; Christoffels, Vincent M 5 ; Marc-Philip, Hitz 2 ; Milewicz, Dianna M 6 ; Posthuma Daniëlle 4 ; Meijers-Heijboer Hanne 16 ; Postma, Alex V 17 ; Mathijssen, Inge B 18 1 Amsterdam UMC, University of Amsterdam, Department of Clinical Genetics, Amsterdam, The Netherlands (GRID:grid.7177.6) (ISNI:0000000084992262); VU University, Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Amsterdam, The Netherlands (GRID:grid.12380.38) (ISNI:0000 0004 1754 9227)
2 Universitätsklinikum Schleswig-Holstein Kiel, Department of Congenital Heart Disease and Pediatric Cardiology, Kiel, Germany (GRID:grid.412468.d) (ISNI:0000 0004 0646 2097)
3 VU University, Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Amsterdam, The Netherlands (GRID:grid.12380.38) (ISNI:0000 0004 1754 9227); Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Alzheimer Center Amsterdam, Department of Neurology, Amsterdam, The Netherlands (GRID:grid.484519.5)
4 VU University, Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Amsterdam, The Netherlands (GRID:grid.12380.38) (ISNI:0000 0004 1754 9227)
5 Amsterdam UMC, University of Amsterdam, Department of Medical Biology, Amsterdam, The Netherlands (GRID:grid.7177.6) (ISNI:0000000084992262)
6 University of Texas Health Science Center at Houston, Department of Internal Medicine, McGovern Medical School, Houston, USA (GRID:grid.267308.8) (ISNI:0000 0000 9206 2401)
7 University of Amsterdam, Department of Pediatric Cardiology, Emma Children’s Hospital, Amsterdam UMC, Amsterdam, The Netherlands (GRID:grid.7177.6) (ISNI:0000000084992262)
8 Amsterdam UMC, University of Amsterdam, Department of Clinical and Experimental Cardiology, Amsterdam, The Netherlands (GRID:grid.7177.6) (ISNI:0000000084992262)
9 Amsterdam UMC, University of Amsterdam, Department of Pathology, Amsterdam, The Netherlands (GRID:grid.7177.6) (ISNI:0000000084992262)
10 Amsterdam UMC, Vrije Universiteit Medisch Centrum, Department of Clinical Genetics, Amsterdam, The Netherlands (GRID:grid.16872.3a) (ISNI:0000 0004 0435 165X)
11 University of Nottingham, Queen’s Medical Centre, School of Life Sciences, Nottingham, United Kingdom (GRID:grid.16872.3a)
12 East Midlands Congenital Heart Centre and University of Leicester, Glenfield Hospital, Leicester, United Kingdom (GRID:grid.412925.9) (ISNI:0000 0004 0400 6581)
13 Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom (GRID:grid.10306.34) (ISNI:0000 0004 0606 5382)
14 University of Erlangen-Nürnberg, Department of Pediatric Cardiology, Erlangen, Germany (GRID:grid.5330.5) (ISNI:0000 0001 2107 3311)
15 Pediatric Cardiology, German Heart Center Berlin, Department of Congenital Heart Disease, Berlin, Germany (GRID:grid.418209.6) (ISNI:0000 0001 0000 0404); DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany (GRID:grid.452396.f) (ISNI:0000 0004 5937 5237)
16 Amsterdam UMC, University of Amsterdam, Department of Clinical Genetics, Amsterdam, The Netherlands (GRID:grid.7177.6) (ISNI:0000000084992262); Amsterdam UMC, Vrije Universiteit Medisch Centrum, Department of Clinical Genetics, Amsterdam, The Netherlands (GRID:grid.16872.3a) (ISNI:0000 0004 0435 165X)
17 Amsterdam UMC, University of Amsterdam, Department of Clinical Genetics, Amsterdam, The Netherlands (GRID:grid.7177.6) (ISNI:0000000084992262); Amsterdam UMC, University of Amsterdam, Department of Medical Biology, Amsterdam, The Netherlands (GRID:grid.7177.6) (ISNI:0000000084992262)
18 Amsterdam UMC, University of Amsterdam, Department of Clinical Genetics, Amsterdam, The Netherlands (GRID:grid.7177.6) (ISNI:0000000084992262)