Arrhythmia Variant Associations and Reclassifications in the eMERGE-III Sequencing Study
Andrew M Glazer, Giovanni Davogustto, Christian M Shaffer, Carlos G Vanoye, Reshma R Desai, Eric H Farber-Eger, Ozan Dikilitas, Ning Shang, Jennifer A Pacheco, Tao Yang, Ayesha Muhammad, Jonathan D Mosley, Sara L Van Driest, Quinn S Wells, Lauren Lee Shaffer, Olivia R Kalash, Yuko Wada, Sarah Bland, Zachary T Yoneda, Devyn W Mitchell, Brett M Kroncke, Iftikhar J Kullo, Gail P Jarvik, Adam S Gordon, Eric B Larson, Teri A Manolio, Tooraj Mirshahi, Jonathan Z Luo, Daniel Schaid, Bahram Namjou, Tarek Alsaied, Rajbir Singh, Ashutosh Singhal, Cong Liu, Chunhua Weng, George Hripcsak, James D Ralston, Elizabeth M McNally, Wendy K Chung, David S Carrell, Kathleen A Leppig, Hakon Hakonarson, Patrick Sleiman, Sunghwan Sohn, Joseph Glessner, eMERGE Network, Joshua Denny, Wei-Qi Wei, Alfred L George Jr, M Benjamin Shoemaker, Dan M Roden, Andrew M Glazer, Giovanni Davogustto, Christian M Shaffer, Carlos G Vanoye, Reshma R Desai, Eric H Farber-Eger, Ozan Dikilitas, Ning Shang, Jennifer A Pacheco, Tao Yang, Ayesha Muhammad, Jonathan D Mosley, Sara L Van Driest, Quinn S Wells, Lauren Lee Shaffer, Olivia R Kalash, Yuko Wada, Sarah Bland, Zachary T Yoneda, Devyn W Mitchell, Brett M Kroncke, Iftikhar J Kullo, Gail P Jarvik, Adam S Gordon, Eric B Larson, Teri A Manolio, Tooraj Mirshahi, Jonathan Z Luo, Daniel Schaid, Bahram Namjou, Tarek Alsaied, Rajbir Singh, Ashutosh Singhal, Cong Liu, Chunhua Weng, George Hripcsak, James D Ralston, Elizabeth M McNally, Wendy K Chung, David S Carrell, Kathleen A Leppig, Hakon Hakonarson, Patrick Sleiman, Sunghwan Sohn, Joseph Glessner, eMERGE Network, Joshua Denny, Wei-Qi Wei, Alfred L George Jr, M Benjamin Shoemaker, Dan M Roden
Abstract
Background: Sequencing Mendelian arrhythmia genes in individuals without an indication for arrhythmia genetic testing can identify carriers of pathogenic or likely pathogenic (P/LP) variants. However, the extent to which these variants are associated with clinically meaningful phenotypes before or after return of variant results is unclear. In addition, the majority of discovered variants are currently classified as variants of uncertain significance, limiting clinical actionability.
Methods: The eMERGE-III study (Electronic Medical Records and Genomics Phase III) is a multicenter prospective cohort that included 21 846 participants without previous indication for cardiac genetic testing. Participants were sequenced for 109 Mendelian disease genes, including 10 linked to arrhythmia syndromes. Variant carriers were assessed with electronic health record-derived phenotypes and follow-up clinical examination. Selected variants of uncertain significance (n=50) were characterized in vitro with automated electrophysiology experiments in HEK293 cells.
Results: As previously reported, 3.0% of participants had P/LP variants in the 109 genes. Herein, we report 120 participants (0.6%) with P/LP arrhythmia variants. Compared with noncarriers, arrhythmia P/LP carriers had a significantly higher burden of arrhythmia phenotypes in their electronic health records. Fifty-four participants had variant results returned. Nineteen of these 54 participants had inherited arrhythmia syndrome diagnoses (primarily long-QT syndrome), and 12 of these 19 diagnoses were made only after variant results were returned (0.05%). After in vitro functional evaluation of 50 variants of uncertain significance, we reclassified 11 variants: 3 to likely benign and 8 to P/LP.
Conclusions: Genome sequencing in a large population without indication for arrhythmia genetic testing identified phenotype-positive carriers of variants in congenital arrhythmia syndrome disease genes. As the genomes of large numbers of people are sequenced, the disease risk from rare variants in arrhythmia genes can be assessed by integrating genomic screening, electronic health record phenotypes, and in vitro functional studies.
Registration: URL: https://www.
Clinicaltrials: gov; Unique identifier; NCT03394859.
Keywords: arrhythmias; cardiac; electronic health records; electrophysiology; genetic testing; long QT syndrome.
Conflict of interest statement
Conflict of Interest Disclosures:
EMM consults for Amgen, Avidity, AstraZeneca, Cytokinetics, Invitae, 4D Molecular Therapeutics, Janssen, Pfizer and Tenaya Therapeutics; she is the founder of Ikaika Therapeutics. ALG is a paid member of Amgen Scientific Advisory Board for Cardiometabolic Disorders, and a recipient of industry sponsored research grant from Tevard Biosciences (unrelated science). None of these activities are related to the content of this work.
Figures
![Fig. 1:. Penetrance of arrhythmia variants by…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/8940719/bin/nihms-1778916-f0001.jpg)
Fig. 2:. ECG interval associations and frequency…
Fig. 2:. ECG interval associations and frequency of LQTS diagnoses
A-D) Comparison between individuals with…
Fig. 3:. Return of variant results
Abbreviations:…
Fig. 3:. Return of variant results
Abbreviations: DCM—Dilated cardiomyopathy; Atrial Fib—Atrial Fibrillation; PVC—Premature Ventricular Contractions;…
Fig. 4:. Percentage of variant carriers with…
Fig. 4:. Percentage of variant carriers with arrhythmia phenotypes
Text columns indicate gene, variant name,…
Fig. 5:. In vitro functional characterization of…
Fig. 5:. In vitro functional characterization of KCNQ1 and SCN5A variants
A. Representative homotetramer current-voltage…
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- Multicenter Study
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Arrhythmias, Cardiac* / diagnosis
- Arrhythmias, Cardiac* / genetics
- Genetic Predisposition to Disease
- Genetic Testing* / methods
- Genomics
- HEK293 Cells
- Humans
- Phenotype
- Prospective Studies
- ClinicalTrials.gov/NCT03394859
- T32 HG008341/HG/NHGRI NIH HHS/United States
- U01 HG008657/HG/NHGRI NIH HHS/United States
- U01 HG008666/HG/NHGRI NIH HHS/United States
- U01 HG008680/HG/NHGRI NIH HHS/United States
- R00 HG010904/HG/NHGRI NIH HHS/United States
- U01 HG008685/HG/NHGRI NIH HHS/United States
- U01 HG006379/HG/NHGRI NIH HHS/United States
- S10 OD025281/OD/NIH HHS/United States
- U01 HG008676/HG/NHGRI NIH HHS/United States
- UL1 TR000445/TR/NCATS NIH HHS/United States
- U01 HG008672/HG/NHGRI NIH HHS/United States
- UL1 TR001422/TR/NCATS NIH HHS/United States
- U01 HG008684/HG/NHGRI NIH HHS/United States
- K99 HG010904/HG/NHGRI NIH HHS/United States
- U01 HG008679/HG/NHGRI NIH HHS/United States
- R01 HL128075/HL/NHLBI NIH HHS/United States
- R01 HL122010/HL/NHLBI NIH HHS/United States
- T32 GM007347/GM/NIGMS NIH HHS/United States
- R00 HL135442/HL/NHLBI NIH HHS/United States
- P30 DK114857/DK/NIDDK NIH HHS/United States
- U01 HG008673/HG/NHGRI NIH HHS/United States
- U01 HG008664/HG/NHGRI NIH HHS/United States
- U01 HG011181/HG/NHGRI NIH HHS/United States
- U01 HG008701/HG/NHGRI NIH HHS/United States
- R01 HL149826/HL/NHLBI NIH HHS/United States
- Full Text Sources
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![Fig. 2:. ECG interval associations and frequency…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/8940719/bin/nihms-1778916-f0002.jpg)
Fig. 3:. Return of variant results
Abbreviations:…
Fig. 3:. Return of variant results
Abbreviations: DCM—Dilated cardiomyopathy; Atrial Fib—Atrial Fibrillation; PVC—Premature Ventricular Contractions;…
Fig. 4:. Percentage of variant carriers with…
Fig. 4:. Percentage of variant carriers with arrhythmia phenotypes
Text columns indicate gene, variant name,…
Fig. 5:. In vitro functional characterization of…
Fig. 5:. In vitro functional characterization of KCNQ1 and SCN5A variants
A. Representative homotetramer current-voltage…
![Fig. 3:. Return of variant results](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/8940719/bin/nihms-1778916-f0003.jpg)
![Fig. 4:. Percentage of variant carriers with…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/8940719/bin/nihms-1778916-f0004.jpg)
![Fig. 5:. In vitro functional characterization of…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/8940719/bin/nihms-1778916-f0005.jpg)
Source: PubMed