@article{89e96e442b2d4c16902b8718d8c57abc,
title = "Arrhythmia Variant Associations and Reclassifications in the eMERGE-III Sequencing Study",
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",
author = "Glazer, {Andrew M.} and Giovanni Davogustto and Shaffer, {Christian M.} and Vanoye, {Carlos G.} and Desai, {Reshma R.} and Farber-Eger, {Eric H.} and Ozan Dikilitas and Ning Shang and Pacheco, {Jennifer A.} and Tao Yang and Ayesha Muhammad and Mosley, {Jonathan D.} and {Van Driest}, {Sara L.} and Wells, {Quinn S.} and Shaffer, {Lauren Lee} and Kalash, {Olivia R.} and Yuko Wada and Sarah Bland and Yoneda, {Zachary T.} and Mitchell, {Devyn W.} and Kroncke, {Brett M.} and Kullo, {Iftikhar J.} and Jarvik, {Gail P.} and Gordon, {Adam S.} and Larson, {Eric B.} and Manolio, {Teri A.} and Tooraj Mirshahi and Luo, {Jonathan Z.} and Daniel Schaid and Bahram Namjou and Tarek Alsaied and Rajbir Singh and Ashutosh Singhal and Cong Liu and Chunhua Weng and George Hripcsak and Ralston, {James D.} and Mcnally, {Elizabeth M.} and Chung, {Wendy K.} and Carrell, {David S.} and Leppig, {Kathleen A.} and Hakon Hakonarson and Patrick Sleiman and Sunghwan Sohn and Joseph Glessner and Joshua Denny and Wei, {Wei Qi} and George, {Alfred L.} and Shoemaker, {M. Benjamin} and Roden, {Dan M.}",
note = "Funding Information: Dr McNally consults for Amgen, Avidity, AstraZeneca, Cytokinetics, Invitae, 4D Molecular Therapeutics, Janssen, Pfizer and Tenaya Therapeutics; she is the founder of Ikaika Therapeutics. Dr George is a paid member of Amgen Scientific Advisory Board for Cardiometabolic Disorders, and a recipient of an industry-sponsored research grant from Tevard Biosciences (unrelated science). None of these activities are related to the content of this work. The other authors report no conflicts. Funding Information: This project used datasets obtained for the eMERGE Network (Phase III). This phase of the eMERGE Network was initiated and funded by the National Human Genome Research Institute through the following grants: U01HG8657 (Kaiser Permanente Washington/University of Washington); U01HG8685 (Brigham and Women{\textquoteright}s Hospital); U01HG8672 (Vanderbilt University Medical Center); U01HG8666 (Cincinnati Children{\textquoteright}s Hospital Medical Center); U01HG6379 (Mayo Clinic); U01HG8679 (Geisinger Clinic); U01HG8680 (Columbia University Irving Medical Center); U01HG8684 (Children{\textquoteright}s Hospital of Philadelphia); U01HG8673 (Northwestern University); U01HG8701 (Vanderbilt University Medical Center serving as the Coordinating Center); U01HG8676 (Partners Healthcare/Broad Institute); and U01HG8664 (Baylor College of Medicine). This research was also funded by National Institutes of Health grants K99 HG010904 (to Dr Glazer), R01 HL149826 (to Dr Roden), R01 HL128075, R01 HL122010 (to Dr George), S10 OD025281, and American Heart Association SFRN grants (to Drs McNally and Davogustto). Electrocardiographic data at Vanderbilt University Medical Center were obtained using Vanderbilt{\textquoteright}s Synthetic Derivative. The Synthetic Derivative resource is supported by Clinical and Translational Science Awards award No. UL1TR000445 from the National Center for Advancing Translational Sciences. The contents of this publication are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the National Institutes of Health. Publisher Copyright: {\textcopyright} 2022 Lippincott Williams and Wilkins. All rights reserved.",
year = "2022",
month = mar,
day = "22",
doi = "10.1161/CIRCULATIONAHA.121.055562",
language = "English (US)",
volume = "145",
pages = "877--891",
journal = "Circulation",
issn = "0009-7322",
publisher = "Lippincott Williams and Wilkins",
number = "12",
}