Clinical Genetic Risk Variants Inform a Functional Protein Interaction Network for Tetralogy of Fallot-Reference-Cited by-同舟云学术

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

Published:2021-08 Issue:4 Volume:14 Page:
ISSN:2574-8300
Container-title:Circulation: Genomic and Precision Medicine
language:en
Short-container-title:Circ: Genomic and Precision Medicine

Author:

Reuter Miriam S.¹²³^ORCID,Chaturvedi Rajiv R.⁴⁵⁶^ORCID,Jobling Rebekah K.⁵⁷⁸,Pellecchia Giovanna²^ORCID,Hamdan Omar²,Sung Wilson W.L.²^ORCID,Nalpathamkalam Thomas²^ORCID,Attaluri Pratyusha⁹^ORCID,Silversides Candice K.¹⁰,Wald Rachel M.⁴¹⁰,Marshall Christian R.²⁸¹¹^ORCID,Williams Simon G.¹²¹³^ORCID,Keavney Bernard D.¹²¹³,Thiruvahindrapuram Bhooma²,Scherer Stephen W.²³¹⁴¹⁵^ORCID,Bassett Anne S.¹⁶¹⁰¹⁷¹⁸^ORCID

Affiliation:

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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

General Medicine

Link

https://www.ahajournals.org/doi/pdf/10.1161/CIRCGEN.121.003410

Reference82 articles.

1. Global birth prevalence of congenital heart defects 1970–2017: updated systematic review and meta-analysis of 260 studies

2. Tetralogy of Fallot

3. Diaz-Frias, J, Guillaume, M. Tetralogy of Fallot. StatPearls; 2020.

4. Tetralogy of Fallot. The first 300 years.;Neill CA;Tex Heart Inst J,1994

5. History of Our Understanding of the Causes of Congenital Heart Disease

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