Genome Medicine (Oct 2023)
Beyond gene-disease validity: capturing structured data on inheritance, allelic requirement, disease-relevant variant classes, and disease mechanism for inherited cardiac conditions
- Katherine S. Josephs,
- Angharad M. Roberts,
- Pantazis Theotokis,
- Roddy Walsh,
- Philip J. Ostrowski,
- Matthew Edwards,
- Andrew Fleming,
- Courtney Thaxton,
- Jason D. Roberts,
- Melanie Care,
- Wojciech Zareba,
- Arnon Adler,
- Amy C. Sturm,
- Rafik Tadros,
- Valeria Novelli,
- Emma Owens,
- Lucas Bronicki,
- Olga Jarinova,
- Bert Callewaert,
- Stacey Peters,
- Tom Lumbers,
- Elizabeth Jordan,
- Babken Asatryan,
- Neesha Krishnan,
- Ray E. Hershberger,
- C. Anwar A. Chahal,
- Andrew P. Landstrom,
- Cynthia James,
- Elizabeth M. McNally,
- Daniel P. Judge,
- Peter van Tintelen,
- Arthur Wilde,
- Michael Gollob,
- Jodie Ingles,
- James S. Ware
Affiliations
- Katherine S. Josephs
- National Heart and Lung Institute, Imperial College London
- Angharad M. Roberts
- National Heart and Lung Institute, Imperial College London
- Pantazis Theotokis
- National Heart and Lung Institute, Imperial College London
- Roddy Walsh
- Amsterdam University Medical Centre, University of Amsterdam, Heart Center, Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences
- Philip J. Ostrowski
- Great Ormond Street Hospital, NHS Foundation Trust
- Matthew Edwards
- Clinical Genetics & Genomics Lab, Royal Brompton and Harefield Hospitals, Guy’s and St Thomas’ NHS Foundation Trust
- Andrew Fleming
- Clinical Genetics & Genomics Lab, Royal Brompton and Harefield Hospitals, Guy’s and St Thomas’ NHS Foundation Trust
- Courtney Thaxton
- Department of Genetics, University of North Carolina at Chapel Hill
- Jason D. Roberts
- Population Health Research Institute, McMaster University, and Hamilton Health Sciences
- Melanie Care
- Department of Molecular Genetics, University of Toronto
- Wojciech Zareba
- Clinical Cardiovascular Research Center, University of Rochester
- Arnon Adler
- Division of Cardiology, Peter Munk Cardiac Centre, University Health Network and Department of Medicine, University of Toronto
- Amy C. Sturm
- 23andMe, Genomic Health
- Rafik Tadros
- Cardiovascular Genetics Center, Montreal Heart Institute, and Faculty of Medicine, Université de Montréal
- Valeria Novelli
- Unit of Immunology and Functional Genomics, Centro Cardiologico Monzino IRCCS
- Emma Owens
- Department of Genetics, University of North Carolina at Chapel Hill
- Lucas Bronicki
- Department of Pathology and Laboratory Medicine, University of Ottawa
- Olga Jarinova
- Department of Pathology and Laboratory Medicine, University of Ottawa
- Bert Callewaert
- Center for Medical Genetics, Ghent University Hospital
- Stacey Peters
- Department of Cardiology and Genomic Medicine, Royal Melbourne Hospital
- Tom Lumbers
- Barts Health & University College London Hospitals NHS Trusts
- Elizabeth Jordan
- Divisions of Human Genetics and Cardiovascular Medicine, The Ohio State University
- Babken Asatryan
- Department of Cardiology, Inselspital, Bern University Hospital, University of Bern
- Neesha Krishnan
- Centre for Population Genomics, Garvan Institute of Medical Research, and UNSW Sydney
- Ray E. Hershberger
- Divisions of Human Genetics and Cardiovascular Medicine, The Ohio State University
- C. Anwar A. Chahal
- Center for Inherited Cardiovascular Diseases, WellSpan Health
- Andrew P. Landstrom
- Department of Pediatrics and Cell Biology, Duke University School of Medicine
- Cynthia James
- Johns Hopkins Center for Inherited Heart Diseases, Department of Medicine, Johns Hopkins University
- Elizabeth M. McNally
- Center for Genetic Medicine, Dept of Medicine (Cardiology), Northwestern University Feinberg School of Medicine
- Daniel P. Judge
- Medical University of South Carolina
- Peter van Tintelen
- Department of Genetics, University Medical Center Utrecht
- Arthur Wilde
- Department of Cardiology, Amsterdam UMC location University of Amsterdam
- Michael Gollob
- Inherited Arrhythmia and Cardiomyopathy Program, Division of Cardiology, University of Toronto
- Jodie Ingles
- Centre for Population Genomics, Garvan Institute of Medical Research, and UNSW Sydney
- James S. Ware
- National Heart and Lung Institute, Imperial College London
- DOI
- https://doi.org/10.1186/s13073-023-01246-8
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 1 – 15
Abstract
Abstract Background As the availability of genomic testing grows, variant interpretation will increasingly be performed by genomic generalists, rather than domain-specific experts. Demand is rising for laboratories to accurately classify variants in inherited cardiac condition (ICC) genes, including secondary findings. Methods We analyse evidence for inheritance patterns, allelic requirement, disease mechanism and disease-relevant variant classes for 65 ClinGen-curated ICC gene-disease pairs. We present this information for the first time in a structured dataset, CardiacG2P, and assess application in genomic variant filtering. Results For 36/65 gene-disease pairs, loss of function is not an established disease mechanism, and protein truncating variants are not known to be pathogenic. Using the CardiacG2P dataset as an initial variant filter allows for efficient variant prioritisation whilst maintaining a high sensitivity for retaining pathogenic variants compared with two other variant filtering approaches. Conclusions Access to evidence-based structured data representing disease mechanism and allelic requirement aids variant filtering and analysis and is a pre-requisite for scalable genomic testing.
Keywords
- Inherited cardiac conditions
- Inheritance
- Allelic requirement
- Disease mechanism
- Gene curation
- Genomic variant filtering
