Dataset Information

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

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.

SUBMITTER: van Walree ES

PROVIDER: S-EPMC8804301 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Publications

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

van Walree Eva S ES Dombrowsky Gregor G Jansen Iris E IE Mirkov Maša Umićević MU Zwart Rob R Ilgun Aho A Guo Dongchuan D Clur Sally-Ann B SB Amin Ahmed S AS Savage Jeanne E JE van der Wal Allard C AC Waisfisz Quinten Q Maugeri Alessandra A Wilsdon Anna A Bu'Lock Frances A FA Hurles Matthew E ME Dittrich Sven S Berger Felix F Audain Martinez Enrique E Christoffels Vincent M VM Hitz Marc-Philip MP Milewicz Dianna M DM Posthuma Daniëlle D Meijers-Heijboer Hanne H Postma Alex V AV Mathijssen Inge B IB

Genetics in medicine : official journal of the American College of Medical Genetics 20200821 1

<h4>Purpose</h4>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.<h4>Methods</h4>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 ...[more]

PMID: 32820247

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Project description:ObjectiveThe objective of this study was to better understand the pathophysiology and underlying genetic mechanisms behind two abdominal aortic aneurysm (AAA) subtypes using computed tomographic imaging in combination with whole genome sequencing.MethodsPatients with a known AAA and European ancestry were included in this investigation and underwent genetic and image analysis. Patients with AAAs and indications of descending thoracic aortic pathology (aortic dissection, penetrating aortic ulcers, intramural hematoma, atheromas, ulcerative plaque, and intramural ulceration, and intimal flaps/tears) were classified as having thoracic aortic disease, grouped together, and compared with patients with an AAA and a normal descending thoracic aorta. Whole genome sequencing was then performed on the 93 patients who had imaging features consistent with thoracic aortic disease and the 126 patients with a normal descending thoracic aorta.ResultsThe results of this study suggest one variant-level, four gene-level, and one gene set-level associations in patients with thoracic aortic disease who also had an AAA. The variant rs79508780 located in TSEN54 achieved study-wide significance (P = 1.71E-06). BATF3 and SMLR1 were significantly associated and EFCAB3 and TAF4 were reached suggestive assocation with a diseased descending thoracic aorta (P = 5.23E-26, P = 1.86E-25, P = 1.54E-05, and P = 8.31E-05, respectively). Gene sets were also compiled using MSigDB and trait-based index single nucleotide variation from major genome-wide association studies. GO_DNA_DOUBLE_STRAND_BREAK_PROCESSING, a gene set related to double-stranded DNA break repair, was significantly associated with thoracic aortic disease in AAA patients (P = 1.80E-06).ConclusionsThis pilot study provides further evidence that an AAA may be the end result of multiple degenerative pathways. Genetic variations in vitamin D signaling, cholesterol metabolism, extracellular matrix breakdown, and double-stranded DNA break repair pathways were associated with European patients who had an AAA and thoracic aortic disease. Additionally, this study provides support for the application of a radiogenomic approach for the investigation of other potential pathologies that could lead to the development of an AAA or influence future management decisions. (JVS-Vascular Science.).Clinical relevanceIn this study, we provide evidence that abdominal aortic aneurysms (AAAs) may be a result of multiple pathophysiologies rather than a single disease. We have identified genetic variants involved in vitamin D signaling, cholesterol metabolism, extracellular matrix breakdown, and double-stranded DNA break repair associated with structural defects in the aortic wall in patients with AAAs who are of European descent. Patients with AAAs and structural defects in the thoracic aorta have been previously linked to differential behavior after endovascular aneurysm repair. These patients with wall defects exhibited greater sac regression, a marker of surgical success, after endovascular aneurysm repair. Our study demonstrates the usefulness of a radiogenomic approach for elucidating mechanisms behind the formation and future behavior of AAAs that could aid surgeons in making future procedural and management decisions.

Dataset Information

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

Purpose

Methods

Results

Conclusion

Publications

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

Similar Datasets

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