Haploinsufficiency of vascular endothelial growth factor related signaling genes is associated with tetralogy of Fallot

Genet Med. 2019 Apr;21(4):1001-1007. doi: 10.1038/s41436-018-0260-9.

Miriam S Reuter ¹ ², Rebekah Jobling ¹ ³ ⁴, Rajiv R Chaturvedi ¹ ⁵, Roozbeh Manshaei ¹, Gregory Costain ³, Tracy Heung ⁶, Meredith Curtis ¹, S Mohsen Hosseini ¹, Eriskay Liston ¹ ³, Chelsea Lowther ⁶, Erwin Oechslin ⁷, Heinrich Sticht ⁸, Bhooma Thiruvahindrapuram ² ⁹, Spencer van Mil ⁶, Rachel M Wald ⁵ ⁷, Susan Walker ² ⁹, Christian R Marshall ² ⁴ ¹⁰ ¹¹, Candice K Silversides ⁷, Stephen W Scherer ² ⁹ ¹⁰ ¹², Raymond H Kim ¹ ³ ¹³, Anne S Bassett ¹⁴ ¹⁵ ¹⁶ ¹⁷

Affiliations

1 Ted Rogers Centre for Heart Research, Cardiac Genome Clinic, The Hospital for Sick Children, Toronto, Ontario, Canada.
2 The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.
3 Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada.
4 Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
5 Labatt Heart Centre, Division of Cardiology, The Hospital for Sick Children, Toronto, Ontario, Canada.
6 Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
7 Division of Cardiology, Toronto Congenital Cardiac Centre for Adults at the Peter Munk Cardiac Centre, Department of Medicine, University Health Network, Toronto, Ontario, Canada.
8 Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
9 Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
10 Centre for Genetic Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
11 Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
12 Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
13 Fred A. Litwin Family Centre in Genetic Medicine, University Health Network, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
14 Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada. [email protected].
15 Division of Cardiology, Toronto Congenital Cardiac Centre for Adults at the Peter Munk Cardiac Centre, Department of Medicine, University Health Network, Toronto, Ontario, Canada. [email protected].
16 The Dalglish Family 22q Clinic for Adults with 22q11.2 Deletion Syndrome, Department of Psychiatry, and Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada. [email protected].
17 Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada. [email protected].

PMID: 30232381 DOI: 10.1038/s41436-018-0260-9

Abstract

Purpose: To determine disease-associated single-gene variants in conotruncal defects, particularly tetralogy of Fallot (TOF).

Methods: We analyzed for rare loss-of-function and deleterious variants in FLT4 (VEGFR3/Flt-4) and other genes in the vascular endothelial growth factor (VEGF) pathway, as part of a genome sequencing study involving 175 adults with TOF from a single site.

Results: We identified nine (5.1%) probands with novel FLT4 variants: seven loss-of-function, including an 8-kb deletion, and two predicted damaging. In ten other probands we found likely disruptive variants in VEGF-related genes: VEGFR2/KDR/Flk-1 (VEGFR2; two stopgain and two nonsynonymous variants), VEGFA, FGD5, BCAR1, IQGAP1, FOXO1, and PRDM1. Detection of VEGF-related variants (19/175, 10.9%) was associated with an increased prevalence of absent pulmonary valve (26.3% vs. 3.4%, p < 0.0001) and right aortic arch (52.6% vs. 29.1%, p = 0.029). Extracardiac anomalies were rare. In an attempt to replicate findings, we identified three loss-of-function or damaging variants in FLT4, VEGFR2/KDR/Flk-1, and IQGAP1 in ten independent families with TOF.

Conclusion: Loss-of-function variants in FLT4 and VEGFR2/KDR/Flk-1 contribute substantially to the genetic basis of TOF. The findings support dysregulated VEGF signaling as a novel mechanism contributing to the pathogenesis of TOF.

Keywords

FLT4; VEGF; congenital heart disease; conotruncal defects; genome sequencing; haploinsufficiency; tetralogy of Fallot.

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