ArticleGenetics in medicine : official journal of the American College of Medical Genetics2023
Continuous Bayesian variant interpretation accounts for incomplete penetrance among Mendelian cardiac channelopathies.
Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 18 citations in OpenAlex.
- MultimodalCirculation · 2026Article
- Automated patch clamp data improve variant classification and penetrance stratification for SCN5A-Brugada syndrome.European heart journal · 2026Article
- Machine learning-guided risk stratification for long QT syndrome genetic variants with hiPSC-derived cardiomyocytes.Cardiovascular research · 2026Article
- Structural Evaluation ofCirculation. Genomic and precision medicine · 2026Article
- The functional landscape of coding variation in the familial hypercholesterolemia geneScience (New York, N.Y.) · 2026Article
- Mapping the Functional Landscape ofmedRxiv : the preprint server for health sciences · 2025Article
- High-throughput screens identify genotype-specific therapeutics for channelopathies.JCI insight · 2025Article
- Secondary structure transitions and dual PIP2 binding define cardiac KCNQ1-KCNE1 channel gating.Cell research · 2025Article
- Properties of Heterochannels Kv(1.1-1.2)International journal of molecular sciences · 2025Article
- Using large-scale population-based data to improve disease risk assessment of clinical variants.Nature genetics · 2025Review
- Article
- Targeting the ICirculation research · 2024Article
- Multiplexed Assays of Variant Effect and Automated Patch-clamping ImprovemedRxiv : the preprint server for health sciences · 2024Article
- Harnessing human genetics and stem cells for precision cardiovascular medicine.Cell genomics · 2024Review
Corrections and comments
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Authors and funding
19 authors at 7 institutions in 4 countries.
Funding
Abstract
purposeThe congenital Long QT Syndrome (LQTS) and Brugada Syndrome (BrS) are Mendelian autosomal dominant diseases that frequently precipitate fatal cardiac arrhythmias. Incomplete penetrance is a barrier to clinical management of heterozygotes harboring variants in the major implicated disease genes KCNQ1, KCNH2, and SCN5A. We apply and evaluate a Bayesian penetrance estimation strategy that accounts for this phenomenon.
methodsWe generated Bayesian penetrance models for KCNQ1-LQT1 and SCN5A-LQT3 using variant-specific features and clinical data from the literature, international arrhythmia genetic centers, and population controls. We analyzed the distribution of posterior penetrance estimates across 4 genotype-phenotype relationships and compared continuous estimates with ClinVar annotations. Posterior estimates were mapped onto protein structure.
resultsBayesian penetrance estimates of KCNQ1-LQT1 and SCN5A-LQT3 are empirically equivalent to 10 and 5 clinically phenotype heterozygotes, respectively. Posterior penetrance estimates were bimodal for KCNQ1-LQT1 and KCNH2-LQT2, with a higher fraction of missense variants with high penetrance among KCNQ1 variants. There was a wide distribution of variant penetrance estimates among identical ClinVar categories. Structural mapping revealed heterogeneity among "hot spot" regions and featured high penetrance estimates for KCNQ1 variants in contact with calmodulin and the S6 domain.
conclusionsBayesian penetrance estimates provide a continuous framework for variant interpretation.
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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.