The Cardiac Genome Clinic: implementing genome sequencing in pediatric heart disease

Miriam S Reuter; Rajiv R Chaturvedi; Eriskay Liston; Roozbeh Manshaei; Ritu B Aul; Sarah Bowdin; Iris Cohn; Meredith Curtis; Priya Dhir; Robin Z Hayeems; S Mohsen Hosseini; Reem Khan; Linh G Ly; Christian R Marshall; Luc Mertens; John B A Okello; Sergio L Pereira; Akshaya Raajkumar; Mike Seed; Bhooma Thiruvahindrapuram; Stephen W Scherer; Raymond H Kim; Rebekah K Jobling

doi:10.1038/s41436-020-0757-x

The Cardiac Genome Clinic: implementing genome sequencing in pediatric heart disease

Genet Med. 2020 Jun;22(6):1015-1024. doi: 10.1038/s41436-020-0757-x. Epub 2020 Feb 10.

Authors

Miriam S Reuter^#^{1

2

3

4}, Rajiv R Chaturvedi^#^{1

5}, Eriskay Liston^{1

6}, Roozbeh Manshaei¹, Ritu B Aul^{1

6}, Sarah Bowdin^{1

6}, Iris Cohn^{1

7}, Meredith Curtis¹, Priya Dhir^{1

8}, Robin Z Hayeems^{1

9}, S Mohsen Hosseini¹, Reem Khan¹, Linh G Ly^{10

11

12}, Christian R Marshall^{3

13

14}, Luc Mertens^{5

11

12}, John B A Okello¹, Sergio L Pereira³, Akshaya Raajkumar³, Mike Seed^{5

11

12}, Bhooma Thiruvahindrapuram^{3

4}, Stephen W Scherer^{3

4

15}, Raymond H Kim^{16

17

18}, Rebekah K Jobling^{19

20

21}

Affiliations

¹ Ted Rogers Centre for Heart Research, Cardiac Genome Clinic, The Hospital for Sick Children, Toronto, ON, Canada.
² CGEn, The Hospital for Sick Children, Toronto, ON, Canada.
³ The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, Canada.
⁴ Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
⁵ Labatt Heart Centre, Division of Cardiology, The Hospital for Sick Children, Toronto, ON, Canada.
⁶ Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada.
⁷ Divisions of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, ON, Canada.
⁸ Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
⁹ Program in Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, ON, Canada.
¹⁰ Division of Neonatology, The Hospital for Sick Children, Toronto, ON, Canada.
¹¹ Department of Paediatrics, The Hospital for Sick Children, Toronto, ON, Canada.
¹² Department of Paediatrics, University of Toronto, Toronto, ON, Canada.
¹³ Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
¹⁴ Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada.
¹⁵ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
¹⁶ Ted Rogers Centre for Heart Research, Cardiac Genome Clinic, The Hospital for Sick Children, Toronto, ON, Canada. Raymond.kim@sickkids.ca.
¹⁷ Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada. Raymond.kim@sickkids.ca.
¹⁸ Fred A. Litwin Family Centre in Genetic Medicine, University Health Network, Department of Medicine, University of Toronto, Toronto, ON, Canada. Raymond.kim@sickkids.ca.
¹⁹ Ted Rogers Centre for Heart Research, Cardiac Genome Clinic, The Hospital for Sick Children, Toronto, ON, Canada. Rebekah.jobling@sickkids.ca.
²⁰ Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada. Rebekah.jobling@sickkids.ca.
²¹ Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada. Rebekah.jobling@sickkids.ca.

^# Contributed equally.

Abstract

Purpose: This study investigated the diagnostic utility of nontargeted genomic testing in patients with pediatric heart disease.

Methods: We analyzed genome sequencing data of 111 families with cardiac lesions for rare, disease-associated variation.

Results: In 14 families (12.6%), we identified causative variants: seven were de novo (ANKRD11, KMT2D, NR2F2, POGZ, PTPN11, PURA, SALL1) and six were inherited from parents with no or subclinical heart phenotypes (FLT4, DNAH9, MYH11, NEXMIF, NIPBL, PTPN11). Outcome of the testing was associated with the presence of extracardiac features (p = 0.02), but not a positive family history for cardiac lesions (p = 0.67). We also report novel plausible gene-disease associations for tetralogy of Fallot/pulmonary stenosis (CDC42BPA, FGD5), hypoplastic left or right heart (SMARCC1, TLN2, TRPM4, VASP), congenitally corrected transposition of the great arteries (UBXN10), and early-onset cardiomyopathy (TPCN1). The identified candidate genes have critical functions in heart development, such as angiogenesis, mechanotransduction, regulation of heart size, chromatin remodeling, or ciliogenesis.

Conclusion: This data set demonstrates the diagnostic and scientific value of genome sequencing in pediatric heart disease, anticipating its role as a first-tier diagnostic test. The genetic heterogeneity will necessitate large-scale genomic initiatives for delineating novel gene-disease associations.

Keywords: ACMG guidelines; congenital heart disease; exome sequencing; gene discovery; genome sequencing.

Publication types

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

MeSH terms

Child
Chromosome Mapping
Exome
Heart Diseases / genetics*
Humans
Mechanotransduction, Cellular
Transposition of Great Vessels