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

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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.

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Most cited references 27

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InterVar: Clinical Interpretation of Genetic Variants by the 2015 ACMG-AMP Guidelines.

Quan Li, Kai Wang (2017)

In 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published updated standards and guidelines for the clinical interpretation of sequence variants with respect to human diseases on the basis of 28 criteria. However, variability between individual interpreters can be extensive because of reasons such as the different understandings of these guidelines and the lack of standard algorithms for implementing them, yet computational tools for semi-automated variant interpretation are not available. To address these problems, we propose a suite of methods for implementing these criteria and have developed a tool called InterVar to help human reviewers interpret the clinical significance of variants. InterVar can take a pre-annotated or VCF file as input and generate automated interpretation on 18 criteria. Furthermore, we have developed a companion web server, wInterVar, to enable user-friendly variant interpretation with an automated interpretation step and a manual adjustment step. These tools are especially useful for addressing severe congenital or very early-onset developmental disorders with high penetrance. Using results from a few published sequencing studies, we demonstrate the utility of InterVar in significantly reducing the time to interpret the clinical significance of sequence variants.

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Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands

Sheng Jin, Jason Homsy, Samir Zaidi … (2017)

Congenital heart disease (CHD) is the leading cause of mortality from birth defects. Exome sequencing of a single cohort of 2,871 CHD probands including 2,645 parent-offspring trios implicated rare inherited mutations in 1.8%, including a recessive founder mutation in GDF1 accounting for ~5% of severe CHD in Ashkenazim, recessive genotypes in MYH6 accounting for ~11% of Shone complex, and dominant FLT4 mutations accounting for 2.3% of Tetralogy of Fallot. De novo mutations (DNMs) accounted for 8% of cases, including ~3% of isolated CHD patients and ~28% with both neurodevelopmental and extra-cardiac congenital anomalies. Seven genes surpassed thresholds for genome-wide significance and 12 genes not previously implicated in CHD had > 70% probability of being disease-related; DNMs in ~440 genes are inferred to contribute to CHD. There was striking overlap between genes with damaging DNMs in probands with CHD and autism.

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Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test

Anath C Lionel, Gregory Costain, Nasim Monfared … (2017)

Purpose Genetic testing is an integral diagnostic component of pediatric medicine. Standard of care is often a time-consuming stepwise approach involving chromosomal microarray analysis and targeted gene sequencing panels, which can be costly and inconclusive. Whole-genome sequencing (WGS) provides a comprehensive testing platform that has the potential to streamline genetic assessments, but there are limited comparative data to guide its clinical use. Methods We prospectively recruited 103 patients from pediatric non-genetic subspecialty clinics, each with a clinical phenotype suggestive of an underlying genetic disorder, and compared the diagnostic yield and coverage of WGS with those of conventional genetic testing. Results WGS identified diagnostic variants in 41% of individuals, representing a significant increase over conventional testing results (24% P = 0.01). Genes clinically sequenced in the cohort (n = 1,226) were well covered by WGS, with a median exonic coverage of 40 × ±8 × (mean ±SD). All the molecular diagnoses made by conventional methods were captured by WGS. The 18 new diagnoses made with WGS included structural and non-exonic sequence variants not detectable with whole-exome sequencing, and confirmed recent disease associations with the genes PIGG, RNU4ATAC, TRIO, and UNC13A. Conclusion WGS as a primary clinical test provided a higher diagnostic yield than conventional genetic testing in a clinically heterogeneous cohort.

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Author and article information

Contributors

Raymond H. Kim:

ORCID: http://orcid.org/0000-0002-2147-8674

Raymond.kim@sickkids.ca

Rebekah K. Jobling: Rebekah.jobling@sickkids.ca

Journal

Journal ID (nlm-ta): Genet Med

Journal ID (iso-abbrev): Genet. Med

Title: Genetics in Medicine

Publisher: Nature Publishing Group US (New York )

ISSN (Print): 1098-3600

ISSN (Electronic): 1530-0366

Publication date (Electronic): 10 February 2020

Publication date PMC-release: 10 February 2020

Publication date (Print): 2020

Volume: 22

Issue: 6

Pages: 1015-1024

Affiliations

[1 ]ISNI 0000 0004 0473 9646, GRID grid.42327.30, Ted Rogers Centre for Heart Research, Cardiac Genome Clinic, The Hospital for Sick Children, ; Toronto, ON Canada

[2 ]ISNI 0000 0004 0473 9646, GRID grid.42327.30, CGEn, The Hospital for Sick Children, ; Toronto, ON Canada

[3 ]ISNI 0000 0004 0473 9646, GRID grid.42327.30, The Centre for Applied Genomics, The Hospital for Sick Children, ; Toronto, ON Canada

[4 ]ISNI 0000 0004 0473 9646, GRID grid.42327.30, Program in Genetics and Genome Biology, The Hospital for Sick Children, ; Toronto, ON Canada

[5 ]ISNI 0000 0004 0473 9646, GRID grid.42327.30, Labatt Heart Centre, Division of Cardiology, The Hospital for Sick Children, ; Toronto, ON Canada

[6 ]ISNI 0000 0004 0473 9646, GRID grid.42327.30, Division of Clinical and Metabolic Genetics, , The Hospital for Sick Children, ; Toronto, ON Canada

[7 ]ISNI 0000 0004 0473 9646, GRID grid.42327.30, Divisions of Clinical Pharmacology and Toxicology, , The Hospital for Sick Children, ; Toronto, ON Canada

[8 ]ISNI 0000 0001 2157 2938, GRID grid.17063.33, Faculty of Medicine, , University of Toronto, ; Toronto, ON Canada

[9 ]ISNI 0000 0004 0473 9646, GRID grid.42327.30, Program in Child Health Evaluative Sciences, The Hospital for Sick Children, ; Toronto, ON Canada

[10 ]ISNI 0000 0004 0473 9646, GRID grid.42327.30, Division of Neonatology, , The Hospital for Sick Children, ; Toronto, ON Canada

[11 ]ISNI 0000 0004 0473 9646, GRID grid.42327.30, Department of Paediatrics, , The Hospital for Sick Children, ; Toronto, ON Canada

[12 ]ISNI 0000 0001 2157 2938, GRID grid.17063.33, Department of Paediatrics, , University of Toronto, ; Toronto, ON Canada

[13 ]ISNI 0000 0001 2157 2938, GRID grid.17063.33, Laboratory Medicine and Pathobiology, , University of Toronto, ; Toronto, ON Canada

[14 ]ISNI 0000 0004 0473 9646, GRID grid.42327.30, Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, ; Toronto, ON Canada

[15 ]ISNI 0000 0001 2157 2938, GRID grid.17063.33, Department of Molecular Genetics, , University of Toronto, ; Toronto, ON Canada

[16 ]ISNI 0000 0001 2157 2938, GRID grid.17063.33, Fred A. Litwin Family Centre in Genetic Medicine, , University Health Network, Department of Medicine, University of Toronto, ; Toronto, ON Canada

Author information

Miriam S. Reuter http://orcid.org/0000-0001-8662-6685

Raymond H. Kim http://orcid.org/0000-0002-2147-8674

Article

Publisher ID: 757

DOI: 10.1038/s41436-020-0757-x

PMC ID: 7272322

PubMed ID: 32037394

SO-VID: 2ffe1f77-148e-443c-a04f-4b18445facfb

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 1 October 2019

Date revision received : 24 January 2020

Date accepted : 27 January 2020

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ScienceOpen disciplines: Genetics

Keywords: genome sequencing,exome sequencing,congenital heart disease,gene discovery,acmg guidelines

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ScienceOpen disciplines: Genetics

Keywords: genome sequencing, exome sequencing, congenital heart disease, gene discovery, acmg guidelines

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

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Abstract

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Genome Integrity

Most cited references 27

InterVar: Clinical Interpretation of Genetic Variants by the 2015 ACMG-AMP Guidelines.

Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands

Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test

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