Clinical Genetic Risk Variants Inform a Functional Protein Interaction Network for Tetralogy of Fallot

Miriam S Reuter; Rajiv R Chaturvedi; Rebekah K Jobling; Giovanna Pellecchia; Omar Hamdan; Wilson W L Sung; Thomas Nalpathamkalam; Pratyusha Attaluri; Candice K Silversides; Rachel M Wald; Christian R Marshall; Simon G Williams; Bernard D Keavney; Bhooma Thiruvahindrapuram; Stephen W Scherer; Anne S Bassett

doi:10.1161/CIRCGEN.121.003410

Clinical Genetic Risk Variants Inform a Functional Protein Interaction Network for Tetralogy of Fallot

Circ Genom Precis Med. 2021 Aug;14(4):e003410. doi: 10.1161/CIRCGEN.121.003410. Epub 2021 Jul 30.

Authors

Miriam S Reuter^{1

2

3}, Rajiv R Chaturvedi^{4

5

6}, Rebekah K Jobling^{5

7

8}, Giovanna Pellecchia², Omar Hamdan², Wilson W L Sung², Thomas Nalpathamkalam², Pratyusha Attaluri⁹, Candice K Silversides¹⁰, Rachel M Wald^{4

10}, Christian R Marshall^{2

8

11}, Simon G Williams^{12

13}, Bernard D Keavney^{12

13}, Bhooma Thiruvahindrapuram², Stephen W Scherer^{2

3

14

15}, Anne S Bassett^{16

10

17

18}

Affiliations

¹ CGEn (M.S.R.), The Hospital for Sick Children, Toronto, ON, Canada.
² Center for Applied Genomics (M.S.R., G.P., O.H., W.W.L.S., T.N., C.R.M., B.T., S.W.S.), The Hospital for Sick Children, Toronto, ON, Canada.
³ Program in Genetics and Genome Biology (M.S.R., S.W.S.), The Hospital for Sick Children, Toronto, ON, Canada.
⁴ Labatt Family Heart Center (R.R.C., R.M.W.), The Hospital for Sick Children, Toronto, ON, Canada.
⁵ Ted Rogers Center for Heart Research, Cardiac Genome Clinic (R.R.C., R.K.J.), The Hospital for Sick Children, Toronto, ON, Canada.
⁶ Ontario Fetal Center, Mount Sinai Hospital, Toronto, ON, Canada (R.R.C.).
⁷ Division of Clinical and Metabolic Genetics (R.K.J.), The Hospital for Sick Children, Toronto, ON, Canada.
⁸ Genome Diagnostics, Department of Paediatric Laboratory Medicine (R.K.J., C.R.M.), The Hospital for Sick Children, Toronto, ON, Canada.
⁹ Medical Genomics Program, Department of Molecular Genetics (P.A.), University of Toronto.
¹⁰ Division of Cardiology, Department of Medicine, Toronto Congenital Cardiac Center for Adults at the Peter Munk Cardiac Center (C.K.S., R.M.W., A.S.B.), and Toronto General Research Institute, University Health Network, ON, Canada.
¹¹ Laboratory Medicine and Pathobiology (C.R.M.), University of Toronto.
¹² Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom (S.G.W., B.D.K.).
¹³ Manchester University NHS Foundation Trust, Manchester Academic Health Science Center, United Kingdom (S.G.W., B.D.K.).
¹⁴ Department of Molecular Genetics (S.W.S.), University of Toronto.
¹⁵ McLaughlin Center (S.W.S.), University of Toronto.
¹⁶ Department of Psychiatry (A.S.B.), University of Toronto.
¹⁷ Department of Psychiatry, The Dalglish Family 22q Clinic for Adults With 22q11.2 Deletion Syndrome (A.S.B.), and Toronto General Research Institute, University Health Network, ON, Canada.
¹⁸ Clinical Genetics Research Program, Center for Addiction and Mental Health, University of Toronto, Toronto, ON, Canada (A.S.B.).

Abstract

Background: Tetralogy of Fallot (TOF)-the most common cyanotic heart defect in newborns-has evidence of multiple genetic contributing factors. Identifying variants that are clinically relevant is essential to understand patient-specific disease susceptibility and outcomes and could contribute to delineating pathomechanisms.

Methods: Using a clinically driven strategy, we reanalyzed exome sequencing data from 811 probands with TOF, to identify rare loss-of-function and other likely pathogenic variants in genes associated with congenital heart disease.

Results: We confirmed a major contribution of likely pathogenic variants in FLT4 (VEGFR3 [vascular endothelial growth factor receptor 3]; n=14) and NOTCH1 (n=10) and identified 1 to 3 variants in each of 21 other genes, including ATRX, DLL4, EP300, GATA6, JAG1, NF1, PIK3CA, RAF1, RASA1, SMAD2, and TBX1. In addition, multiple loss-of-function variants provided support for 3 emerging congenital heart disease/TOF candidate genes: KDR (n=4), IQGAP1 (n=3), and GDF1 (n=8). In total, these variants were identified in 63 probands (7.8%). Using the 26 composite genes in a STRING protein interaction enrichment analysis revealed a biologically relevant network (P=3.3×10^-16), with VEGFR2 (vascular endothelial growth factor receptor 2; KDR) and NOTCH1 (neurogenic locus notch homolog protein 1) representing central nodes. Variants associated with arrhythmias/sudden death and heart failure indicated factors that could influence long-term outcomes.

Conclusions: The results are relevant to precision medicine for TOF. They suggest considerable clinical yield from genome-wide sequencing, with further evidence for KDR (VEGFR2) as a congenital heart disease/TOF gene and for VEGF (vascular endothelial growth factor) and Notch signaling as mechanisms in human disease. Harnessing the genetic heterogeneity of single gene defects could inform etiopathogenesis and help prioritize novel candidate genes for TOF.

Keywords: genetic variation; genomics; heart defects, congenital; receptors, vascular endothelial growth factor; tetralogy of Fallot.

Publication types

Clinical Trial
Research Support, Non-U.S. Gov't

MeSH terms

Exome Sequencing
Female
Genetic Predisposition to Disease*
Genome-Wide Association Study
Humans
Infant, Newborn
Male
Protein Interaction Maps*
Tetralogy of Fallot / genetics*

Abstract

Publication types

MeSH terms

Grants and funding