ArticleCirculation. Arrhythmia and electrophysiology2015
Identification and Functional Characterization of a Novel CACNA1C-Mediated Cardiac Disorder Characterized by Prolonged QT Intervals With Hypertrophic Cardiomyopathy, Congenital Heart Defects, and Sudden Cardiac Death.
Article in Circulation. Arrhythmia and electrophysiology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 56 papers, 2 of them syntheses that pooled it.
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Who cites it
56 citing papers in PubMed, 2 syntheses or guidelines pooled it, 92 citations in OpenAlex.
- Diagnosis and management of very rare primary arrhythmia syndromes in children and adults: a Clinical Consensus Statement of the European Heart Rhythm Association of the ESC and the Association of Cardiovascular Nursing & Allied Professions of the ESC, endorsed by the Association for European Paediatric and Congenital Cardiology.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2026Guideline
- Geno- and phenotypic characteristics and clinical outcomes ofFrontiers in cardiovascular medicine · 2022Pooled it
- Review
- Rethinking Childhood-Onset Hypertrophic Cardiomyopathy: A Review of Molecular Mechanisms and Unique Therapy Considerations.Journal of cardiovascular development and disease · 2025Review
- Evaluation of CACNA1C-Positive Patients Evaluated in a Tertiary Genetic Heart Rhythm Clinic.Journal of cardiovascular translational research · 2025Article
- CACNA1C c.1255G>A Variant Is Associated With an Atypical Timothy Syndrome Phenotype.JACC. Case reports · 2025Article
- Calcium channel-coupled transcription factors facilitate direct nuclear signaling.Research square · 2025Article
- Genes Associated With Hypertrophic Cardiomyopathy: A Reappraisal by the ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel.Journal of the American College of Cardiology · 2025Article
- The modulation of calcium and chloride channels induces cardiomyocytes from human pluripotent stem cells.International journal of biological sciences · 2025Article
- Whole genome sequencing of families diagnosed with cardiac channelopathies reveals structural variants missed by whole exome sequencing.Journal of human genetics · 2024Article
- ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel: Reappraisal of Genes associated with Hypertrophic Cardiomyopathy.medRxiv : the preprint server for health sciences · 2024Article
- Genetic Mutations and Mitochondrial Redox Signaling as Modulating Factors in Hypertrophic Cardiomyopathy: A Scoping Review.International journal of molecular sciences · 2024Article
- Structural bases of inhibitory mechanism of CaNature communications · 2024Article
- Human Genetics of Cardiac Arrhythmias.Advances in experimental medicine and biology · 2024Review
- The H2Bub1-deposition complex is required for human and mouse cardiogenesis.Development (Cambridge, England) · 2023Article
- Clinical presentation of calmodulin mutations: the International Calmodulinopathy Registry.European heart journal · 2023Observational
- Hypertrophic cardiomyopathy and long QT syndrome in cardiac-only Timothy syndrome.HeartRhythm case reports · 2023Article
- Study of pathogenic genes in a pedigree with familial dilated cardiomyopathy.World journal of clinical cases · 2023Article
- Palmitoylation of the pore-forming subunit of Ca(v)1.2 controls channel voltage sensitivity and calcium transients in cardiac myocytes.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Dysregulated Cell Homeostasis and miRNAs in Human iPSC-Derived Cardiomyocytes from a Propionic Acidemia Patient with Cardiomyopathy.International journal of molecular sciences · 2023Article
Corrections and comments
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
Abstract
backgroundA portion of sudden cardiac deaths can be attributed to structural heart diseases, such as hypertrophic cardiomyopathy (HCM) or cardiac channelopathies such as long-QT syndrome (LQTS); however, the underlying molecular mechanisms are distinct. Here, we identify a novel CACNA1C missense mutation with mixed loss-of-function/gain-of-function responsible for a complex phenotype of LQTS, HCM, sudden cardiac death, and congenital heart defects. METHODS AND
resultsWhole exome sequencing in combination with Ingenuity variant analysis was completed on 3 affected individuals and 1 unaffected individual from a large pedigree with concomitant LQTS, HCM, and congenital heart defects and identified a novel CACNA1C mutation, p.Arg518Cys, as the most likely candidate mutation. Mutational analysis of exon 12 of CACNA1C was completed on 5 additional patients with a similar phenotype of LQTS plus a personal or family history of HCM-like phenotypes and identified 2 additional pedigrees with mutations at the same position, p.Arg518Cys/His. Whole cell patch clamp technique was used to assess the electrophysiological effects of the identified mutations in CaV1.2 and revealed a complex phenotype, including loss of current density and inactivation in combination with increased window and late current.
conclusionsThrough whole exome sequencing and expanded cohort screening, we identified a novel genetic substrate p.Arg518Cys/His-CACNA1C, in patients with a complex phenotype including LQTS, HCM, and congenital heart defects annotated as cardiac-only Timothy syndrome. Our electrophysiological studies, identification of mutations at the same amino acid position in multiple pedigrees, and cosegregation with disease in these pedigrees provide evidence that p.Arg518Cys/His is the pathogenic substrate for the observed phenotype.
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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.