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

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

doi:10.1038/s41436-020-00939-4

Cited by 10 publications

(5 citation statements)

References 37 publications

(45 reference statements)

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“…Although, several genes have been shown to be altered in syndromic and non-syndromic cases with CHD and TAA (e.g. HEY2 [36], MYH11 and NOTCH1 [37]), among the 10 genes significant in our analysis for TAA, CHD and the combined scenario, none has been reported previously to be associated with either CHD or TAA. Given the limited data size and only accessing CNV calls from TAA cases, future studies looking at CNV and DNV in both phenotypes are required to establish stronger genotype-phenotype correlation to better understand a possibly shared genetic architecture for the two disease entities.…”

Section: Plos Geneticscontrasting

confidence: 56%

Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease

et al. 2021

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Numerous genetic studies have established a role for rare genomic variants in Congenital Heart Disease (CHD) at the copy number variation (CNV) and de novo variant (DNV) level. To identify novel haploinsufficient CHD disease genes, we performed an integrative analysis of CNVs and DNVs identified in probands with CHD including cases with sporadic thoracic aortic aneurysm. We assembled CNV data from 7,958 cases and 14,082 controls and performed a gene-wise analysis of the burden of rare genomic deletions in cases versus controls. In addition, we performed variation rate testing for DNVs identified in 2,489 parent-offspring trios. Our analysis revealed 21 genes which were significantly affected by rare CNVs and/or DNVs in probands. Fourteen of these genes have previously been associated with CHD while the remaining genes (FEZ1, MYO16, ARID1B, NALCN, WAC, KDM5B and WHSC1) have only been associated in small cases series or show new associations with CHD. In addition, a systems level analysis revealed affected protein-protein interaction networks involved in Notch signaling pathway, heart morphogenesis, DNA repair and cilia/centrosome function. Taken together, this approach highlights the importance of re-analyzing existing datasets to strengthen disease association and identify novel disease genes and pathways.

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Section: Plos Geneticscontrasting

confidence: 56%

Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease

et al. 2021

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“…In OCTN2-deficient cardiomyocytes, transcription factors crucial for cardiomyocyte development and congenital heart defects, including HAND1 , HEY2 , FOXM1 , MEF2A , NR2F2 and GATA6 , are significantly downregulated ( Fig. 3 K) [ [36] , [37] , [38] , [39] , [40] , [41] ]. Additionally, we employed GSVA to study alterations in signaling pathways between WT and the OCTN2-deficient group ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Unraveling cardiomyocyte responses and intercellular communication alterations in primary carnitine deficiency cardiomyopathy via single-nucleus RNA sequencing

Yin,

Ye,

Chen

et al. 2024

Heliyon

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“…This was accompanied by varied cardiovascular malformations, such as hypoplastic endocardial cushions, which led to perinatal death, and were linked to the downstream target Hey2 [89]. Hey2 plays a key role during heart development [90,91], and genetic variants have been associated with congenital heart disease [92]. Conditional knockout of Ezh2 in cardiomyocytes halted mouse neonatal heart regeneration due to impeded proliferation of cardiomyocytes and H3K27me3 modifications.…”

Section: H3k27 Methylationmentioning

confidence: 99%

The Roles of Histone Lysine Methyltransferases in Heart Development and Disease

Zhu

Leemput

Han

2023

JCDD

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Epigenetic marks regulate the transcriptomic landscape by facilitating the structural packing and unwinding of the genome, which is tightly folded inside the nucleus. Lysine-specific histone methylation is one such mark. It plays crucial roles during development, including in cell fate decisions, in tissue patterning, and in regulating cellular metabolic processes. It has also been associated with varying human developmental disorders. Heart disease has been linked to deregulated histone lysine methylation, and lysine-specific methyltransferases (KMTs) are overrepresented, i.e., more numerous than expected by chance, among the genes with variants associated with congenital heart disease. This review outlines the available evidence to support a role for individual KMTs in heart development and/or disease, including genetic associations in patients and supporting cell culture and animal model studies. It concludes with new advances in the field and new opportunities for treatment.

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

Cited by 10 publications

References 37 publications

Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease

Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease

Unraveling cardiomyocyte responses and intercellular communication alterations in primary carnitine deficiency cardiomyopathy via single-nucleus RNA sequencing

The Roles of Histone Lysine Methyltransferases in Heart Development and Disease

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