ArticleGenetics in medicine : official journal of the American College of Medical Genetics2022
Dominant negative effects of SCN5A missense variants.
Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
What it found
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Who cites it
17 citing papers in PubMed, 26 citations in OpenAlex.
- Biochemical assessment of α-α-subunit interactions of NaScientific reports · 2026Article
- Phenotypic Severity ofCirculation. Arrhythmia and electrophysiology · 2026Article
- High-Throughput Methods for Variant Functional Assessment in Cardiac Disease.Circulation. Genomic and precision medicine · 2026Review
- Characterization of the R893C NaFrontiers in cardiovascular medicine · 2026Article
- Voltage-gated sodium channels in excitable cells as drug targets.Nature reviews. Drug discovery · 2025Review
- A Rare Noncoding Enhancer Variant inCirculation · 2025Article
- ParSE-seq: a calibrated multiplexed assay to facilitate the clinical classification of putative splice-altering variants.Nature communications · 2024Article
- Multisite Validation of a Functional Assay to AdjudicateCirculation. Genomic and precision medicine · 2024Article
- Variable Penetrance and Expressivity of a Rare Pore Loss-of-Function Mutation (p.L889V) of Nav1.5 Channels in Three Spanish Families.International journal of molecular sciences · 2024Article
- Multi-site validation of a functional assay to adjudicatemedRxiv : the preprint server for health sciences · 2023Article
- Deep mutational scanning of proteins in mammalian cells.Cell reports methods · 2023Review
- Prokaryotic voltage-gated sodium channels are more effective than endogenous NaAmerican journal of physiology. Heart and circulatory physiology · 2023Article
- Brugada Syndrome: More than a Monogenic Channelopathy.Biomedicines · 2023Review
- Functional Characterisation of the RareInternational journal of molecular sciences · 2023Article
- Automated Patch-Clamp and Induced Pluripotent Stem Cell-Derived Cardiomyocytes: A Synergistic Approach in the Study of Brugada Syndrome.International journal of molecular sciences · 2023Review
- Development of automated patch clamp assays to overcome the burden of variants of uncertain significance in inheritable arrhythmia syndromes.Frontiers in physiology · 2023Review
- Genomic and Non-Genomic Regulatory Mechanisms of the Cardiac Sodium Channel in Cardiac Arrhythmias.International journal of molecular sciences · 2022Review
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
purposeUp to 30% of patients with Brugada syndrome (BrS) carry loss-of-function (LoF) variants in the cardiac sodium channel gene SCN5A encoding for the protein Na
methodsWe identified 35 LoF variants (<10% of wild type [WT] peak current) and 15 partial LoF variants (10%-50% of WT peak current) that we assessed for dominant negative effects. SCN5A variants were studied in HEK293T cells, alone or in heterozygous coexpression with WT SCN5A using automated patch clamp. To assess the clinical risk, we compared the prevalence of dominant negative vs putative haploinsufficient (frameshift, splice, or nonsense) variants in a BrS consortium and the Genome Aggregation Database population database.
resultsIn heterozygous expression with WT, 32 of 35 LoF and 6 of 15 partial LoF variants showed reduction to <75% of WT-alone peak current, showing a dominant negative effect. Individuals with dominant negative LoF variants had an elevated disease burden compared with the individuals with putative haploinsufficient variants (2.7-fold enrichment in BrS cases, P = .019).
conclusionMost SCN5A missense LoF variants exert a dominant negative effect. This class of variant confers an especially high burden of BrS.
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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.