Using Whole Genome Sequence Findings to Assess gene-disease Causality in Cardiomyopathy and Arrhythmia Patients

Abstract

Aim: The genetic etiologies of cardiomyopathies and arrhythmias have not been fully elucidated. Materials & methods: Research findings from genome analyses in a cardiomyopathy and arrhythmia cohort were gathered. Gene-disease relationships from two databases were compared with patient phenotypes. A literature review was conducted for genes with limited evidence. Results: Of 43 genes with candidate findings from 18 cases, 23.3% of genes had never been curated, 15.0% were curated for cardiomyopathies, 16.7% for arrhythmias and 31.3% for other conditions. 25.5% of candidate findings were curated for the patient's specific phenotype with 11.8% having definitive evidence. MYH6 and TPCN1 were flagged for recuration. Conclusion: Findings from genome sequencing in disease cohorts may be useful to guide gene-curation efforts.

Keywords:

• arrhythmia
• cardiomyopathy
• gene curation
• gene-disease validity
• MYH6
• TPCN1
• whole genome sequencing

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at:www.tandfonline.com/doi/full/10.2217/fca-2023-0082

Author contributions

AR Krishnan: Substantial contributions to the conception and design of the work; analysis and interpretation of data; data curation; drafting of the work; final approval of the version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. MLB Schwartz: Substantial contributions to the conception and design of the work; interpretation of data; revising work critically for content; supervision; final approval of the version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. C Somerville: Substantial contributions to the design of the work; analysis of data; revising work critically for content; final approval of the version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Q Ding: Substantial contributions to the design of the work; analysis of data; revising work critically for content; final approval of the version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. RH Kim: Substantial contributions to the design of the work; revising work critically for content; supervision; project administration; funding acquisition; final approval of the version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Acknowledgments

The authors would like to thank all the patients and their families for participating in this study. This work was funded by the Ted Rogers Centre for Heart Research.

Financial disclosure

This research was funded by the McLaughlin Accelerator Grant, grant number MC-2017-06. This research is supported by the Ted Rogers Centre for Heart Research. This research was also funded by the Starbucks Coffee Company Endowment Fund. The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The study was conducted in accordance with the Declaration of Helsinki and approved by the Research Ethics Boards (REB) at the Hospital for Sick Children, titled The Cardiac Genome Clinic: a collaborative model for identifying genetic basis of heart failure in the whole-genome era (REB 1000053844 and start date: 2016-05-06) and the University Health Network, titled The Cardiac Genome Clinic: a collaborative model for identifying genetic basis of heart failure in the whole-genome era (REB 16–6282 and start date: 2018-05-08). This work was funded by the Ted Rogers Centre for Heart Research. Informed consent has been obtained from the study participants, and an explanation of how the consent was obtained is included in the manuscript.

Data sharing statement

The data presented in this study are available on request from the corresponding author. The data are not publicly available to maintain the privacy of enrolled patients.