ArticleThe Journal of clinical investigation2018
Physiological genomics identifies genetic modifiers of long QT syndrome type 2 severity.
Article in The Journal of clinical investigation, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed, 68 citations in OpenAlex.
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- K2P channels as emerging therapeutic targets for pain: insights from functional studies and transcriptomic analyses.Frontiers in pharmacology · 2026Review
- Structure-Function Relationships of KAdvances in experimental medicine and biology · 2026Review
- A New High Penetrant Intronic Pathogenic Variant Related to Long QT Syndrome Type 2.Journal of clinical medicine · 2025Article
- Transformative Potential of Induced Pluripotent Stem Cells in Congenital Heart Disease Research and Treatment.Children (Basel, Switzerland) · 2025Review
- Induced Pluripotent Stem Cells in Congenital Long QT Syndrome: Research Progress and Clinical Applications.Reviews in cardiovascular medicine · 2025Review
- Ion occupancy of the selectivity filter controls opening of a cytoplasmic gate in the KNature communications · 2024Article
- From genes to clinical management: A comprehensive review of long QT syndrome pathogenesis and treatment.Heart rhythm O2 · 2024Review
- Reclassification of a likely pathogenic Dutch founder variant in KCNH2; implications of reduced penetrance.Human molecular genetics · 2023Article
- The Advantages, Challenges, and Future of Human-Induced Pluripotent Stem Cell Lines in Type 2 Long QT Syndrome.Journal of cardiovascular translational research · 2023Review
- Precision medicine for long QT syndrome: patient-specific iPSCs take the lead.Expert reviews in molecular medicine · 2023Review
- Modeling incomplete penetrance in arrhythmogenic cardiomyopathy by human induced pluripotent stem cell derived cardiomyocytes.Computational and structural biotechnology journal · 2023Article
- A need for exhaustive and standardized characterization of ion channels activity. The case of KFrontiers in physiology · 2023Review
- Genome Editing and Inherited Cardiac Arrhythmias.Advances in experimental medicine and biology · 2023Article
- From a Single Cell to a Whole Human Liver: Disease Modeling and Transplantation.Seminars in liver disease · 2022Article
- A Novel Locus on 6p21.2 for Cancer Treatment-Induced Cardiac Dysfunction Among Childhood Cancer Survivors.Journal of the National Cancer Institute · 2022Article
- Uncovering the Genetic Etiology of the (Posttherapy) Broken Heart.Journal of the National Cancer Institute · 2022Article
- Mutation-Specific Differences in Kv7.1 (International journal of molecular sciences · 2022Review
- How Functional Genomics Can Keep Pace With VUS Identification.Frontiers in cardiovascular medicine · 2022Review
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
Congenital long QT syndrome (LQTS) is an inherited channelopathy associated with life-threatening arrhythmias. LQTS type 2 (LQT2) is caused by mutations in KCNH2, which encodes the potassium channel hERG. We hypothesized that modifier genes are partly responsible for the variable phenotype severity observed in some LQT2 families. Here, we identified contributors to variable expressivity in an LQT2 family by using induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and whole exome sequencing in a synergistic manner. We found that iPSC-CMs recapitulated the clinical genotype-phenotype discordance in vitro. Importantly, iPSC-CMs derived from the severely affected LQT2 patients displayed prolonged action potentials compared with cells from mildly affected first-degree relatives. The iPSC-CMs derived from all patients with hERG R752W mutation displayed lower IKr amplitude. Interestingly, iPSC-CMs from severely affected mutation-positive individuals exhibited greater L-type Ca2+ current. Whole exome sequencing identified variants of KCNK17 and the GTP-binding protein REM2, providing biologically plausible explanations for this variable expressivity. Genome editing to correct a REM2 variant reversed the enhanced L-type Ca2+ current and prolonged action potential observed in iPSC-CMs from severely affected individuals. Thus, our findings showcase the power of combining complementary physiological and genomic analyses to identify genetic modifiers and potential therapeutic targets of a monogenic disorder. Furthermore, we propose that this strategy can be deployed to unravel myriad confounding pathologies displaying variable expressivity.
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Registered trials
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.