An Evidence-Based Assessment of Genes in Dilated Cardiomyopathy-Reference-Cited by-同舟云学术

An Evidence-Based Assessment of Genes in Dilated Cardiomyopathy

Published:2021-05-05 Issue: Volume: Page:
ISSN:0009-7322
Container-title:Circulation
language:en
Short-container-title:Circulation

Author:

Jordan Elizabeth¹^ORCID,Peterson Laiken¹,Ai Tomohiko¹^ORCID,Asatryan Babken²^ORCID,Bronicki Lucas³,Brown Emily⁴,Celeghin Rudy⁵^ORCID,Edwards Matthew⁶,Fan Judy⁷,Ingles Jodie⁸^ORCID,James Cynthia A.⁴^ORCID,Jarinova Olga³,Johnson Renee⁹^ORCID,Judge Daniel P.¹⁰^ORCID,Lahrouchi Najim¹¹^ORCID,Lekanne Deprez Ronald H.¹²^ORCID,Lumbers R. Thomas¹³^ORCID,Mazzarotto Francesco¹⁴,Medeiros Domingo Argelia¹⁵^ORCID,Miller Rebecca L.¹⁶,Morales Ana¹⁷^ORCID,Murray Brittney⁴^ORCID,Peters Stacey¹⁸,Pilichou Kalliopi⁵^ORCID,Protonotarios Alexandros¹⁹^ORCID,Semsarian Christopher²⁰^ORCID,Shah Palak¹⁶^ORCID,Syrris Petros¹⁹^ORCID,Thaxton Courtney²¹^ORCID,van Tintelen J. Peter²²^ORCID,Walsh Roddy¹¹^ORCID,Wang Jessica⁷^ORCID,Ware James²³^ORCID,Hershberger Ray E.²⁴^ORCID

Affiliation:

1. Division of Human Genetics, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH

2. Department for Cardiology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

3. Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada & Department of Laboratory and Pathology Medicine, University of Ottawa, Canada

4. Johns Hopkins University Department of Medicine, Division of Cardiology, Baltimore, MD

5. University of Padua, Department of Cardiac-Thoracic-Vascular Sciences and Public Health, Padua, Italy

6. Clinical Genetics & Genomics Laboratory, Royal Brompton and Harefield NHS Foundation Trust, London, UK

7. Department of Medicine, University of California, Los Angeles, CA

8. Cardio Genomics Program at Centenary Institute, The University of Sydney, Sydney, Australia

9. Victor Chang Cardiac Research Institute, Sydney, Australia & Department of Medicine University of New South Wales, Sydney, Australia

10. Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, SC

11. Department of Clinical and Experimental Cardiology, Heart Centre, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands

12. Department of Clinical Genetics, Amsterdam University Medical Center location AMC, the Netherlands

13. Institute of Health Informatics, University College London, London, UK; Health Data Research UK London, University College London, UK; UCL British Heart Foundation Research Accelerator, London, UK

14. Cardiovascular Research Center, Royal Brompton and Harefield Hospitals, NHS Foundation Trust, London, UK; National Heart & Lung Institute, Imperial College London, London, UK; Department of Clinical and Experimental Medicine, University of Florence, Florence, Italy; Cardiomyopathy Unit, Careggi University Hospital, Florence, Italy

15. Swiss DNAlysis Cardiogenetics, Dübendorf, Switzerland

16. Cardiovascular Genomics Center, Inova Heart and Vascular Institute, Falls Church, VA

17. Invitae Corporation, San Francisco, CA

18. Department of Cardiology & Genomic Medicine, Royal Melbourne Hospital, Melbourne, Australia

19. Centre for Heart Muscle Disease, Institute of Cardiovascular Science, University College London, London, UK

20. Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, Sydney, Australia

21. Department of Genetics, University of North Carolina, Chapel Hill, NC

22. Department of Genetics, University Medical Center Utrecht, University of Utrecht, Utrecht, the Netherlands

23. Cardiovascular Research Center, Royal Brompton and Harefield Hospitals, NHS Foundation Trust, London, UK; National Heart & Lung Institute, Imperial College London, London, UK; MRC London Institute for Medical Sciences, Imperial College London, London, UK

24. Division of Human Genetics, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH; Division of Cardiovascular Medicine, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH

Abstract

Background: The cardiomyopathies, classically categorized as hypertrophic (HCM), dilated (DCM), and arrhythmogenic right ventricular (ARVC), each have a signature genetic theme. HCM and ARVC are largely understood as genetic diseases of sarcomere or desmosome proteins, respectively. In contrast, >250 genes spanning more than 10 gene ontologies have been implicated in DCM, representing a complex and diverse genetic architecture. To clarify this, a systematic curation of evidence to establish the relationship of genes with DCM was conducted. Methods: An international Panel with clinical and scientific expertise in DCM genetics evaluated evidence supporting monogenic relationships of genes with idiopathic DCM. The Panel utilized the ClinGen semi-quantitative gene-disease clinical validity classification framework with modifications for DCM genetics to classify genes into categories based on the strength of currently available evidence. Representation of DCM genes on clinically available genetic testing panels was evaluated. Results: Fifty-one genes with human genetic evidence were curated. Twelve genes (23%) from eight gene ontologies were classified as having definitive ( BAG3, DES, FLNC, LMNA, MYH7, PLN, RBM20, SCN5A, TNNC1, TNNT2, TTN ) or strong ( DSP ) evidence. Seven genes (14%) ( ACTC1, ACTN2, JPH2, NEXN, TNNI3, TPM1, VCL ) including two additional ontologies were classified as moderate evidence; these genes are likely to emerge as strong or definitive with additional evidence. Of these 19 genes, six were similarly classified for HCM and three for ARVC. Of the remaining 32 genes (63%), 25 (49%) had limited evidence, 4 (8%) were disputed, 2 (4%) had no disease relationship, and 1 (2%) was supported by animal model data only. Of 16 evaluated clinical genetic testing panels, most definitive genes were included, but panels also included numerous genes with minimal human evidence. Conclusions: In the curation of 51 genes, 19 had high evidence (12 definitive/strong; seven moderate). Notably, these 19 genes only explain a minority of cases, leaving the remainder of DCM genetic architecture incompletely addressed. Clinical genetic testing panels include most high evidence genes, however genes lacking robust evidence are also commonly included. We recommend that high evidence DCM genes be used for clinical practice and to exercise caution when interpreting variants in variable evidence DCM genes.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine

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