Article in European heart journal, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
0numbers the graph read from it
0cells of the map it votes in
5citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
2 · The registry
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
5 · Who and what money
Authors and funding
13 authors.
Matthew J O'NeillDepartment of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
Joanne G MaMark Cowley Lidwill Research Program in Cardiac Electrophysiology, Victor Chang Cardiac Research Institute, 405 Liverpool St, Darlinghurst, NSW, Australia.ORCID 0009-0001-1616-5681
Jessa L AldridgeVanderbilt Center for Arrhythmia Research and Therapeutics (VanCART), Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, 2215B Garland Ave, 1235 Medical Research Building IV, Nashville, TN, USA.ORCID 0000-0002-6071-9581
Joseph F SolusVanderbilt Center for Arrhythmia Research and Therapeutics (VanCART), Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, 2215B Garland Ave, 1235 Medical Research Building IV, Nashville, TN, USA.ORCID 0009-0009-7432-9056
Genevieve R HarveyVanderbilt Center for Arrhythmia Research and Therapeutics (VanCART), Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, 2215B Garland Ave, 1235 Medical Research Building IV, Nashville, TN, USA.
Paige H RobersonVanderbilt Center for Arrhythmia Research and Therapeutics (VanCART), Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, 2215B Garland Ave, 1235 Medical Research Building IV, Nashville, TN, USA.
Julien BarcNantes Université, CNRS, INSERM, l'institut du thorax, IRS-UN, 8 Quai Moncousu, BP 70721, Nantes 44007, France.
Connie R BezzinaEuropean Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart: ERN GUARD-Heart, Amsterdam, The Netherlands.ORCID 0000-0002-0633-3514
Dan M RodenVanderbilt Center for Arrhythmia Research and Therapeutics (VanCART), Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, 2215B Garland Ave, 1235 Medical Research Building IV, Nashville, TN, USA.ORCID 0000-0002-6302-0389
Roddy WalshDepartment of Experimental Cardiology, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands.ORCID 0000-0001-5092-8825
Jamie I VandenbergMark Cowley Lidwill Research Program in Cardiac Electrophysiology, Victor Chang Cardiac Research Institute, 405 Liverpool St, Darlinghurst, NSW, Australia.ORCID 0000-0002-3859-3716
Andrew M GlazerVanderbilt Center for Arrhythmia Research and Therapeutics (VanCART), Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, 2215B Garland Ave, 1235 Medical Research Building IV, Nashville, TN, USA.ORCID 0000-0002-3938-4713
Chai-Ann NgMark Cowley Lidwill Research Program in Cardiac Electrophysiology, Victor Chang Cardiac Research Institute, 405 Liverpool St, Darlinghurst, NSW, Australia.ORCID 0000-0002-3120-5450
Funding
Tumor Immunology and Microenvironment Research ProgramP30CA068485 · NCI · VANDERBILT UNIVERSITY MEDICAL CENTER · PI Ben Ho Park · 1995 to 2026
$172.8M
Translational Analysis CoreP30DK058404 · NIDDK · VANDERBILT UNIVERSITY MEDICAL CENTER · PI MARY Kay WASHINGTON · 2002 to 2026
$29.9M
MEDICAL SCIENTIST TRAINING PROGRAMT32GM007347 · NIGMS · VANDERBILT UNIVERSITY · PI WILLIAMS, CHRISTOPHER S. · 1985 to 2023
$26.3M
Systematically mapping variant effects for cardiovascular genesR01HL164675 · NHLBI · VANDERBILT UNIVERSITY MEDICAL CENTER · PI ASHLEY, EUAN A, RODEN, DAN M · 2022 to 2025
$8.1M
Functional Genomics of Cardiac Sodium Channel VariantsR01HL149826 · NHLBI · VANDERBILT UNIVERSITY MEDICAL CENTER · PI RODEN, DAN M · 2020 to 2023
$2.9M
High-throughput discovery of disease-associated ion channel variantsR35GM150465 · NIGMS · VANDERBILT UNIVERSITY MEDICAL CENTER · PI Andrew M. Glazer · 2023 to 2026
$1.8M
A pipeline for identifying disease-causing variants in transmembrane proteinsR00HG010904 · NHGRI · VANDERBILT UNIVERSITY MEDICAL CENTER · PI GLAZER, ANDREW M. · 2022 to 2024
$737k
Nanion SynchroPatch 384 for Automated, High-throughput ElectrophysiologyS10OD025281 · OD · VANDERBILT UNIVERSITY · PI WEAVER, C DAVID · 2018 to 2018
$571k
Aberrant Splicing in the Cardiac ArrhythmiasF30HL163923 · NHLBI · VANDERBILT UNIVERSITY · PI O'NEILL, MATTHEW · 2022 to 2023
$61k
European CommissionHORIZON-EIC-2022-PATHFINDERCHALLENGES-01HORIZON European Innovation CouncilMedical Research Future Fund: Genomics Health Futures Mission F30HL163923Medical Research Future Fund: Genomics Health Futures Mission MRF2016760Medical Research Future Fund: Genomics Health Futures Mission T32GM007347Nav1.5-CARED 101115295NCI NIH HHS P30 CA068485New South Wales Cardiovascular Disease Senior ScientistNHGRI NIH HHS R00 HG010904NHLBI NIH HHS F30 HL163923NHLBI NIH HHS R01 HL149826NHLBI NIH HHS R01 HL164675NIDDK NIH HHS P30 DK058404NIGMS NIH HHS R35 GM150465NIGMS NIH HHS T32 GM007347NIH HHS R00 HG010904NIH HHS R01 HL149826NIH HHS R01 HL164675NIH HHS R35 GM150465NIH HHS S10 OD025281NIH Shared Instrumentation 1S10OD025281Vanderbilt Digestive Disease Research Center DK058404Vanderbilt Ingram Cancer Center P30 CA68485Vanderbilt Institute of Chemical Biology P30 CA68485
6 · The paper itself
Abstract
BACKGROUND AND
aimsBrugada Syndrome (BrS) is an inherited arrhythmia disorder that causes an elevated risk of sudden cardiac death. Approximately 20% of patients with BrS have rare variants in SCN5A, which encodes the cardiac sodium channel NaV1.5. Genetic workup of BrS is often complicated by SCN5A variants of uncertain significance (VUS) and/or incomplete penetrance. This study deployed an SCN5A-BrS functional assay at cohort scale to facilitate the implementation of genetic and precision medicine.
methodsAll 252 missense and in-frame insertion/deletion SCN5A variants from a previously published large cohort of BrS cases (n = 3335 patients) were analysed using a calibrated high-throughput automated patch-clamp (APC) assay. Variant functional Z-scores were assigned evidence levels ranging from BS3_moderate (normal function) to PS3_strong (loss-of-function), as defined by American College of Medical Genetics and Genomics criteria. Functional evidence was combined with population frequency, hotspot, case counts, protein-length changes, and in silico predictions. Odds ratios of BrS case-control enrichment and penetrance for BrS were calculated from variant frequencies in the BrS cohort and in gnomAD.
resultsMost variants (146/252) were functionally abnormal (Z ≤ -2), with 100 having severe loss-of-function (Z ≤ -4). Functional evidence enabled the reclassification of 110 of 225 VUS; 104 to likely pathogenic and 6 to likely benign. SCN5A variants with loss-of-function were mainly localized to the transmembrane domains, especially the regions comprising the central pore. SCN5A variant penetrance was proportional to the severity of loss-of-function; variants with Z ≤ -6 had penetrance of 24.5% (15.9%-37.7% CI) and an odds ratio of 501 for BrS.
conclusionsThis cohort-scale APC dataset stratifies SCN5A variants found in BrS patients into normal function 'bystander' variants that have a low risk of BrS and loss-of-function variants that have a high risk for BrS. Functional data can be integrated with other criteria to reclassify a substantial fraction of VUS. The dataset helps clarify the SCN5A-BrS relationship and will improve the diagnosis and clinical management of BrS probands and their families.
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.
Automated patch clamp data improve variant classification and penetrance stratification for SCN5A-Brugada syndrome. · full record | OpenQuestion