Rare variants in KDR, encoding VEGF Receptor 2, are associated with tetralogy of Fallot

Škorić‐Milosavljević, Doris; Lahrouchi, Najim; Bosada, Fernanda M.; Dombrowsky, Gregor; Williams, Simon G.; Lesurf, Robert; Tjong, Fleur V.Y.; Walsh, Roddy; Bouchikhi, Ihssane El; Breckpot, Jeroen; Audain, Enrique; Ilgun, Aho; Beekman, Leander; Ratbi, Ilham; Strong, Alanna; Muenke, Maximilian; Heide, Solveig; Muir, Alison M.; Hababa, Mariam; Cross, Laura; Zhou, Dihong; Pastinen, Tomi; Zackai, Elaine H.; Atmani, S.; Ouldim, Karim; Adadi, Najlae; Steindl, Katharina; Rauch, Anita; Brook, David; Wilsdon, Anna; Kuipers, Irene M.; Blom, Nico A.; Mulder, Barbara J.M.; Mefford, Heather C; Keren, Boris; Joset, Pascal; Kruszka, Paul; Thiffault, Isabelle; Sheppard, Sarah E.; Roberts, Amy; Lodder, Elisabeth M.; Keavney, Bernard; Clur, Sally‐Ann B.; Mital, Seema; Hitz, Marc‐Phillip; Christoffels, Vincent M.; Postma, Alex V.; Bezzina, Connie R.

doi:10.1038/s41436-021-01212-y

Cited by 10 publications

(9 citation statements)

References 35 publications

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“…In addition to FLT4, other genes in the vascular endothelial growth factor (VEGF) pathway have been associated with TOF. LOF variants in KDR, encoding the vascular endothelial growth factor receptor 2 (VEGFR2), were identified in TOF cohorts (138) and more recently, exome sequencing in a familial case of TOF and large-scale genetic studies revealed rare variants in KDR in a family with TOF (191). These studies proposed novel mechanisms that dysregulated VEGF signaling contributes to the pathogenesis of TOF.…”

Section: Summary Of Ngs In Large Chd Cohortsmentioning

confidence: 97%

Genetics of congenital heart disease: a narrative review of recent advances and clinical implications

Yasuhara¹,

Garg²

2021

Transl Pediatr

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Congenital heart disease (CHD) is the most common human birth defect and remains a leading cause of mortality in childhood. Although advances in clinical management have improved the survival of children with CHD, adult survivors commonly experience cardiac and non-cardiac comorbidities, which affect quality of life and prognosis. Therefore, the elucidation of genetic etiologies of CHD not only has important clinical implications for genetic counseling of patients and families but may also impact clinical outcomes by identifying at-risk patients. Recent advancements in genetic technologies, including massively parallel sequencing, have allowed for the discovery of new genetic etiologies for CHD. Although variant prioritization and interpretation of pathogenicity remain challenges in the field of CHD genomics, advances in single-cell genomics and functional genomics using cellular and animal models of CHD have the potential to provide novel insights into the underlying mechanisms of CHD and its associated morbidities. In this review, we provide an updated summary of the established genetic contributors to CHD and discuss recent advances in our understanding of the genetic architecture of CHD along with current challenges with the interpretation of genetic variation. Furthermore, we highlight the clinical implications of genetic findings to predict and potentially improve clinical outcomes in patients with CHD.

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Section: Summary Of Ngs In Large Chd Cohortsmentioning

confidence: 97%

Genetics of congenital heart disease: a narrative review of recent advances and clinical implications

Yasuhara¹,

Garg²

2021

Transl Pediatr

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“…An irregular blood flow pattern, chamber hypoplasia, obstructive lesions and aberrant venous and arterial connections found in individuals with CHD results in some of the most interesting and complicated abnormalities in normal heart physiology ( Škorić-Milosavljević et al, 2021 ). The physiological changes surrounding hyper cyanotic incidents consist of either a reduction in systemic vascular resistance or a rise in pulmonary resistance, both of which paticipate to a right-to-left shunt across the VDS ( Mcleod et al, 2018 ; Ho et al, 2019 ); and ( Senst et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

Genetic insights into non-syndromic Tetralogy of Fallot

Althali

Hentges

2022

Front. Physiol.

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Congenital heart defects (CHD) include structural abnormalities of the heart or/and great vessels that are present at birth. CHD affects around 1% of all newborns worldwide. Tetralogy of Fallot (TOF) is the most prevalent cyanotic congenital cardiac abnormality, affecting three out of every 10,000 live infants with a prevalence rate of 5–10% of all congenital cardiac defects. The four hallmark characteristics of TOF are: right ventricular hypertrophy, pulmonary stenosis, ventricular septal defect, and overriding aorta. Approximately 20% of cases of TOF are associated with a known disease or chromosomal abnormality, with the remaining 80% of TOF cases being non-syndromic, with no known aetiology. Relatively few TOF patients have been studied, and little is known about critical causative genes for non-syndromic TOF. However, rare genetic variants have been identified as significant risk factors for CHD, and are likely to cause some cases of TOF. Therefore, this review aims to provide an update on well-characterized genes and the most recent variants identified for non-syndromic TOF.

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“…We speculated that this variant may be the genetic cause of TOF. As a highly heterogeneous disease, previous studies have suggested that rare potential pathogenic variants of genes related to the heart development, such as Filamin A (FLNA), Kinase Insert Domain Receptor (KDR), and NKX2.5 are associated with the occurrence of TOF (12,18,19,23). Recently, several variants in the sarcomere genes such as Myosin Heavy Chain 7 (MYH7) and Myosin Binding Protein C3 (MYBPC3) have been identified in patients with heart diseases (24)(25)(26)(27).…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, further studies on the genetic etiology of TOF were needed to better understand its pathogenesis. In addition, most studies focused on sporadic cases of TOF, and reports on families with TOF patients were relatively limited (14)(15)(16)(17)(18)(19).…”

Section: Introductionmentioning

confidence: 99%

Case Report: Tetralogy of Fallot in a Chinese Family Caused by a Novel Missense Variant of MYOM2

Wang

Xie

et al. 2022

Front. Cardiovasc. Med.

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BackgroundRare genetic variants have been identified to be important contributors to the risk of Tetralogy of Fallot (TOF), the most common cyanotic congenital heart disease (CHD). But relatively limited familial studies with small numbers of TOF cases have been reported to date. In this study, we aimed to identify novel pathogenic genes and variants that caused TOF in a Chinese family using whole exome sequencing (WES).MethodsA Chinese family whose twins were affected by TOF were recruited for this study. A WES was performed for the affected twins, their healthy brother, and parents to identify the potential pathogenic mutated gene(s). Heterozygous variants carried by the twins, but not the unaffected brother, were retained. Public databases were used to assess the frequencies of the selected variants, and online prediction tools were accessed to predict the influences of these variants on protein function. The final candidate variant was further confirmed by Sanger sequencing in other members of the family.ResultsAfter several filtering processes, a heterozygous missense variant in the MYOM2 gene (NM_003970.4:c.3097C>T:p.R1033C) was identified and confirmed by Sanger sequencing in the affected twins and their unaffected father, suggesting an inheritance pattern with incomplete penetrance. The variant was found to be extremely rare in the public databases. Furthermore, the mutated site was highly conserved among mammals, and as shown using multiple online prediction tools, this variant was predicted to be a detrimental variant.ConclusionWe assessed a family with TOF caused by a rare heterozygous missense variant of MYOM2. Our findings not only further confirm the significant role of genetics in the incidence of TOF but also expand the spectrum of the gene variants that lead to TOF.

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Rare variants in KDR, encoding VEGF Receptor 2, are associated with tetralogy of Fallot

Cited by 10 publications

References 35 publications

Genetics of congenital heart disease: a narrative review of recent advances and clinical implications

Genetics of congenital heart disease: a narrative review of recent advances and clinical implications

Genetic insights into non-syndromic Tetralogy of Fallot

Case Report: Tetralogy of Fallot in a Chinese Family Caused by a Novel Missense Variant of MYOM2

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