{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T03:30:39Z","timestamp":1771558239114,"version":"3.50.1"},"reference-count":37,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2024,4,25]],"date-time":"2024-04-25T00:00:00Z","timestamp":1714003200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004837","name":"Ministerio de Ciencia e Innovaci\u00f3n","doi-asserted-by":"publisher","award":["PID2020-118694RB-I00"],"award-info":[{"award-number":["PID2020-118694RB-I00"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"Ministerio de Ciencia e Innovaci\u00f3n","doi-asserted-by":"publisher","award":["S2022\/BMD-7229"],"award-info":[{"award-number":["S2022\/BMD-7229"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"Ministerio de Ciencia e Innovaci\u00f3n","doi-asserted-by":"publisher","award":["CB16\/11\/00303"],"award-info":[{"award-number":["CB16\/11\/00303"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"Ministerio de Ciencia e Innovaci\u00f3n","doi-asserted-by":"publisher","award":["CB16\/11\/00374"],"award-info":[{"award-number":["CB16\/11\/00374"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006541","name":"Comunidad Aut\u00f3noma de Madrid","doi-asserted-by":"publisher","award":["PID2020-118694RB-I00"],"award-info":[{"award-number":["PID2020-118694RB-I00"]}],"id":[{"id":"10.13039\/501100006541","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006541","name":"Comunidad Aut\u00f3noma de Madrid","doi-asserted-by":"publisher","award":["S2022\/BMD-7229"],"award-info":[{"award-number":["S2022\/BMD-7229"]}],"id":[{"id":"10.13039\/501100006541","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006541","name":"Comunidad Aut\u00f3noma de Madrid","doi-asserted-by":"publisher","award":["CB16\/11\/00303"],"award-info":[{"award-number":["CB16\/11\/00303"]}],"id":[{"id":"10.13039\/501100006541","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006541","name":"Comunidad Aut\u00f3noma de Madrid","doi-asserted-by":"publisher","award":["CB16\/11\/00374"],"award-info":[{"award-number":["CB16\/11\/00374"]}],"id":[{"id":"10.13039\/501100006541","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"CIBERCV, Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PID2020-118694RB-I00"],"award-info":[{"award-number":["PID2020-118694RB-I00"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"CIBERCV, Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["S2022\/BMD-7229"],"award-info":[{"award-number":["S2022\/BMD-7229"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"CIBERCV, Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["CB16\/11\/00303"],"award-info":[{"award-number":["CB16\/11\/00303"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"CIBERCV, Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["CB16\/11\/00374"],"award-info":[{"award-number":["CB16\/11\/00374"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>A novel rare mutation in the pore region of Nav1.5 channels (p.L889V) has been found in three unrelated Spanish families that produces quite diverse phenotypic manifestations (Brugada syndrome, conduction disease, dilated cardiomyopathy, sinus node dysfunction, etc.) with variable penetrance among families. We clinically characterized the carriers and recorded the Na+ current (INa) generated by p.L889V and native (WT) Nav1.5 channels, alone or in combination, to obtain further insight into the genotypic\u2013phenotypic relationships in patients carrying SCN5A mutations and in the molecular determinants of the Nav1.5 channel function. The variant produced a strong dominant negative effect (DNE) since the peak INa generated by p.L889V channels expressed in Chinese hamster ovary cells, either alone (\u221269.4 \u00b1 9.0 pA\/pF) or in combination with WT (\u221262.2 \u00b1 14.6 pA\/pF), was significantly (n \u2265 17, p &lt; 0.05) reduced compared to that generated by WT channels alone (\u2212199.1 \u00b1 44.1 pA\/pF). The mutation shifted the voltage dependence of channel activation and inactivation to depolarized potentials, did not modify the density of the late component of INa, slightly decreased the peak window current, accelerated the recovery from fast and slow inactivation, and slowed the induction kinetics of slow inactivation, decreasing the fraction of channels entering this inactivated state. The membrane expression of p.L889V channels was low, and in silico molecular experiments demonstrated profound alterations in the disposition of the pore region of the mutated channels. Despite the mutation producing a marked DNE and reduction in the INa and being located in a critical domain of the channel, its penetrance and expressivity are quite variable among the carriers. Our results reinforce the argument that the incomplete penetrance and phenotypic variability of SCN5A loss-of-function mutations are the result of a combination of multiple factors, making it difficult to predict their expressivity in the carriers despite the combination of clinical, genetic, and functional studies.<\/jats:p>","DOI":"10.3390\/ijms25094686","type":"journal-article","created":{"date-parts":[[2024,4,26]],"date-time":"2024-04-26T05:13:41Z","timestamp":1714108421000},"page":"4686","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Variable Penetrance and Expressivity of a Rare Pore Loss-of-Function Mutation (p.L889V) of Nav1.5 Channels in Three Spanish Families"],"prefix":"10.3390","volume":"25","author":[{"given":"Mar\u00eda","family":"Gallego-Delgado","sequence":"first","affiliation":[{"name":"Department of Cardiology, CSUR Cardiopat\u00edas Familiares, Institute of Biomedical Research of Salamanca (IBSAL), Complejo Asistencial Universitario de Salamanca, Gerencia Regional de Salud de Castilla y Le\u00f3n (SACYL), 37007 Salamaca, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red en Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6124-2236","authenticated-orcid":false,"given":"Anabel","family":"C\u00e1mara-Checa","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red en Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain"},{"name":"Department of Pharmacology, School of Medicine, Instituto de Investigaci\u00f3n Sanitaria Gregorio Mara\u00f1\u00f3n, Universidad Complutense, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcos","family":"Rubio-Alarc\u00f3n","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red en Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain"},{"name":"Department of Pharmacology, School of Medicine, Instituto de Investigaci\u00f3n Sanitaria Gregorio Mara\u00f1\u00f3n, Universidad Complutense, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Heredero-Jung","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, CSUR Cardiopat\u00edas Familiares, Institute of Biomedical Research of Salamanca (IBSAL), Complejo Asistencial Universitario de Salamanca, Gerencia Regional de Salud de Castilla y Le\u00f3n (SACYL), 37007 Salamaca, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"de la Fuente-Blanco","sequence":"additional","affiliation":[{"name":"Department of Cardiology, CSUR Cardiopat\u00edas Familiares, Institute of Biomedical Research of Salamanca (IBSAL), Complejo Asistencial Universitario de Salamanca, Gerencia Regional de Salud de Castilla y Le\u00f3n (SACYL), 37007 Salamaca, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red en Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7706-8818","authenticated-orcid":false,"given":"Josu","family":"Rap\u00fan","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red en Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain"},{"name":"Department of Pharmacology, School of Medicine, Instituto de Investigaci\u00f3n Sanitaria Gregorio Mara\u00f1\u00f3n, Universidad Complutense, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0447-9883","authenticated-orcid":false,"given":"Beatriz","family":"Plata-Izquierdo","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Institute of Biomedical Research of Salamanca (IBSAL), Complejo Asistencial Universitario de Salamanca, Gerencia Regional de Salud de Castilla y Leon (SACYL), CIBERCV, 37007 Salamaca, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4693-842X","authenticated-orcid":false,"given":"Sara","family":"P\u00e9rez-Mart\u00edn","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red en Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain"},{"name":"Department of Pharmacology, School of Medicine, Instituto de Investigaci\u00f3n Sanitaria Gregorio Mara\u00f1\u00f3n, Universidad Complutense, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5070-0070","authenticated-orcid":false,"given":"Jorge","family":"Cebri\u00e1n","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red en Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain"},{"name":"Department of Pharmacology, School of Medicine, Instituto de Investigaci\u00f3n Sanitaria Gregorio Mara\u00f1\u00f3n, Universidad Complutense, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luc\u00eda","family":"Moreno de Redrojo","sequence":"additional","affiliation":[{"name":"Department of Cardiology, CSUR Cardiopat\u00edas Familiares, Institute of Biomedical Research of Salamanca (IBSAL), Complejo Asistencial Universitario de Salamanca, Gerencia Regional de Salud de Castilla y Le\u00f3n (SACYL), 37007 Salamaca, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red en Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bel\u00e9n","family":"Garc\u00eda-Berrocal","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, CSUR Cardiopat\u00edas Familiares, Institute of Biomedical Research of Salamanca (IBSAL), Complejo Asistencial Universitario de Salamanca, Gerencia Regional de Salud de Castilla y Le\u00f3n (SACYL), 37007 Salamaca, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eva","family":"Delp\u00f3n","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red en Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain"},{"name":"Department of Pharmacology, School of Medicine, Instituto de Investigaci\u00f3n Sanitaria Gregorio Mara\u00f1\u00f3n, Universidad Complutense, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pedro L.","family":"S\u00e1nchez","sequence":"additional","affiliation":[{"name":"Department of Cardiology, CSUR Cardiopat\u00edas Familiares, Institute of Biomedical Research of Salamanca (IBSAL), Complejo Asistencial Universitario de Salamanca, Gerencia Regional de Salud de Castilla y Le\u00f3n (SACYL), 37007 Salamaca, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red en Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0486-1740","authenticated-orcid":false,"given":"Eduardo","family":"Villacorta","sequence":"additional","affiliation":[{"name":"Department of Cardiology, CSUR Cardiopat\u00edas Familiares, Institute of Biomedical Research of Salamanca (IBSAL), Complejo Asistencial Universitario de Salamanca, Gerencia Regional de Salud de Castilla y Le\u00f3n (SACYL), 37007 Salamaca, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red en Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6424-9687","authenticated-orcid":false,"given":"Ricardo","family":"Caballero","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red en Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain"},{"name":"Department of Pharmacology, School of Medicine, Instituto de Investigaci\u00f3n Sanitaria Gregorio Mara\u00f1\u00f3n, Universidad Complutense, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1007\/s00395-009-0012-8","article-title":"The Cardiac Sodium Channel Displays Differential Distribution in the Conduction System and Transmural Heterogeneity in the Murine Ventricular Myocardium","volume":"104","author":"Remme","year":"2009","journal-title":"Basic Res. Cardiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1557","DOI":"10.1093\/cvr\/cvaa082","article-title":"Heritable Arrhythmia Syndromes Associated with Abnormal Cardiac Sodium Channel Function: Ionic and Non-Ionic Mechanisms","volume":"116","author":"Rivaud","year":"2020","journal-title":"Cardiovasc. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1038\/s41572-020-0188-7","article-title":"Inherited Cardiac Arrhythmias","volume":"6","author":"Schwartz","year":"2020","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/j.jacep.2018.03.006","article-title":"Clinical Spectrum of SCN5A Mutations: Long QT Syndrome, Brugada Syndrome, and Cardiomyopathy","volume":"4","author":"Wilde","year":"2018","journal-title":"JACC Clin. Electrophysiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2584","DOI":"10.1161\/CIRCULATIONAHA.106.653949","article-title":"Overlap Syndrome of Cardiac Sodium Channel Disease in Mice Carrying the Equivalent Mutation of Human SCN5A-1795insD","volume":"114","author":"Remme","year":"2006","journal-title":"Circulation"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1172\/JCI118445","article-title":"Mapping a Cardiomyopathy Locus to Chromosome 3p22-P25","volume":"97","author":"Olson","year":"1996","journal-title":"J. Clin. Investig."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1082","DOI":"10.1093\/eurheartj\/ehaa942","article-title":"Brugada Syndrome Genetics Is Associated with Phenotype Severity","volume":"42","author":"Ciconte","year":"2021","journal-title":"Eur. Heart J."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.ajhg.2020.05.015","article-title":"High-Throughput Reclassification of SCN5A Variants","volume":"107","author":"Glazer","year":"2020","journal-title":"Am. J. Hum. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2281714","DOI":"10.1080\/19336950.2023.2281714","article-title":"Voltage Gated Sodium and Calcium Channels: Discovery, Structure, Function, and Pharmacology","volume":"17","author":"Catterall","year":"2023","journal-title":"Channels"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e202112995","DOI":"10.1085\/jgp.202112995","article-title":"A Cant\u00fa Syndrome Mutation Produces Dual Effects on KATP Channels by Disrupting Ankyrin B Regulation","volume":"155","author":"Dago","year":"2023","journal-title":"J. Gen. Physiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.cell.2019.11.041","article-title":"Structure of the Cardiac Sodium Channel","volume":"180","author":"Jiang","year":"2020","journal-title":"Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"W296","DOI":"10.1093\/nar\/gky427","article-title":"SWISS-MODEL: Homology Modelling of Protein Structures and Complexes","volume":"46","author":"Waterhouse","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e002095","DOI":"10.1161\/CIRCGEN.118.002095","article-title":"SCN5A (NaV1.5) Variant Functional Perturbation and Clinical Presentation: Variants of a Certain Significance","volume":"11","author":"Kroncke","year":"2018","journal-title":"Circ. Genom. Precis. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1016\/j.hrthm.2012.10.025","article-title":"P.D1690N Nav1.5 Rescues p.G1748D Mutation Gating Defects in a Compound Heterozygous Brugada Syndrome Patient","volume":"10","author":"Barana","year":"2013","journal-title":"Heart Rhythm"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1093\/cvr\/cvs211","article-title":"Dominant-Negative Effect of SCN5A N-Terminal Mutations through the Interaction of Na(v)1.5 \u03b1-Subunits","volume":"96","author":"Clatot","year":"2012","journal-title":"Cardiovasc. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2077","DOI":"10.1038\/s41467-017-02262-0","article-title":"Voltage-Gated Sodium Channels Assemble and Gate as Dimers","volume":"8","author":"Clatot","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"H1250","DOI":"10.1152\/ajpheart.00721.2017","article-title":"Mutant Voltage-Gated Na+ Channels Can Exert a Dominant Negative Effect through Coupled Gating","volume":"315","author":"Clatot","year":"2018","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3847","DOI":"10.1113\/JP284861","article-title":"A Detailed Analysis of Single-Channel Nav1.5 Recordings Does Not Reveal Any Cooperative Gating","volume":"601","author":"Selimi","year":"2023","journal-title":"J. Physiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1016\/j.yjmcc.2005.02.024","article-title":"A Mutation in the Human Cardiac Sodium Channel (E161K) Contributes to Sick Sinus Syndrome, Conduction Disease and Brugada Syndrome in Two Families","volume":"38","author":"Smits","year":"2005","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2757","DOI":"10.1093\/hmg\/ddv036","article-title":"Testing the Burden of Rare Variation in Arrhythmia-Susceptibility Genes Provides New Insights into Molecular Diagnosis for Brugada Syndrome","volume":"24","author":"Karakachoff","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1238","DOI":"10.1016\/j.gim.2022.02.010","article-title":"Dominant Negative Effects of SCN5A Missense Variants","volume":"24","author":"Muhammad","year":"2022","journal-title":"Genet. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2854","DOI":"10.1093\/eurheartj\/ehab254","article-title":"Functionally Validated SCN5A Variants Allow Interpretation of Pathogenicity and Prediction of Lethal Events in Brugada Syndrome","volume":"42","author":"Ishikawa","year":"2021","journal-title":"Eur. Heart J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2195","DOI":"10.1002\/humu.24128","article-title":"Relationship between Sodium Channel Function and Clinical Phenotype in SCN5A Variants Associated with Brugada Syndrome","volume":"41","author":"Pearman","year":"2020","journal-title":"Hum. Mutat."},{"key":"ref_25","first-page":"3925","article-title":"Modifier Genes for Sudden Cardiac Death","volume":"39","author":"Schwartz","year":"2018","journal-title":"Eur. Heart J."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Kroncke, B.M., Smith, D.K., Zuo, Y., Glazer, A.M., Roden, D.M., and Blume, J.D. (2020). A Bayesian Method to Estimate Variant-Induced Disease Penetrance. PLoS Genet., 16.","DOI":"10.1371\/journal.pgen.1008862"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"148093","DOI":"10.1016\/j.gene.2023.148093","article-title":"SCN5A-L256del and L1621F Exhibit Loss-of-Function Properties Related to Autosomal Recessive Congenital Cardiac Disorders Presenting as Sick Sinus Syndrome, Dilated Cardiomyopathy, and Sudden Cardiac Death","volume":"898","author":"Shi","year":"2024","journal-title":"Gene"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1161\/01.RES.0000052672.97759.36","article-title":"Compound Heterozygosity for Mutations (W156X and R225W) in SCN5A Associated with Severe Cardiac Conduction Disturbances and Degenerative Changes in the Conduction System","volume":"92","author":"Bezzina","year":"2003","journal-title":"Circ. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"E416","DOI":"10.1073\/pnas.1612383114","article-title":"Tbx20 Controls the Expression of the KCNH2 Gene and of hERG Channels","volume":"114","author":"Caballero","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1093\/cvr\/cvab045","article-title":"Tbx5 Variants Disrupt Nav1.5 Function Differently in Patients Diagnosed with Brugada or Long QT Syndrome","volume":"118","author":"Tinaquero","year":"2022","journal-title":"Cardiovasc. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e2305135120","DOI":"10.1073\/pnas.2305135120","article-title":"A Gain-of-Function HCN4 Mutant in the HCN Domain Is Responsible for Inappropriate Sinus Tachycardia in a Spanish Family","volume":"120","author":"Perin","year":"2023","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"96291","DOI":"10.1172\/jci.insight.96291","article-title":"Brugada Syndrome Trafficking-Defective Nav1.5 Channels Can Trap Cardiac Kir2.1\/2.2 Channels","volume":"3","author":"Matamoros","year":"2018","journal-title":"JCI Insight"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Dago, M., Crespo-Garc\u00eda, T., C\u00e1mara-Checa, A., Rap\u00fan, J., Rubio-Alarc\u00f3n, M., Mar\u00edn, M., Tamargo, J., Caballero, R., and Delp\u00f3n, E. (2022). Empagliflozin and Dapagliflozin Increase Na+ and Inward Rectifier K+ Current Densities in Human Cardiomyocytes Derived from Induced Pluripotent Stem Cells (hiPSC-CMs). Cells, 11.","DOI":"10.3390\/cells11233707"},{"key":"ref_34","first-page":"324","article-title":"Digenic Heterozigosity in SCN5A and CACNA1C Explains the Variable Expressivity of the Long QT Phenotype in a Spanish Family","volume":"72","author":"Tinaquero","year":"2019","journal-title":"Rev. Esp. Cardiol. (Engl. Ed.)"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/S0014-5793(00)01875-5","article-title":"A Novel SCN5A Mutation Associated with Idiopathic Ventricular Fibrillation without Typical ECG Findings of Brugada Syndrome","volume":"479","author":"Akai","year":"2000","journal-title":"FEBS Lett."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3165","DOI":"10.1161\/01.CIR.99.24.3165","article-title":"Congenital Long-QT Syndrome Caused by a Novel Mutation in a Conserved AcidicDomain of the Cardiac Na+ Channel","volume":"99","author":"Wei","year":"1999","journal-title":"Circulation"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1021\/acs.biochem.6b00798","article-title":"A General Mechanism for the Propagation of Mutational Effects in Proteins","volume":"56","author":"Rajasekaran","year":"2017","journal-title":"Biochemistry"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/9\/4686\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:33:15Z","timestamp":1760106795000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/9\/4686"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,25]]},"references-count":37,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2024,5]]}},"alternative-id":["ijms25094686"],"URL":"https:\/\/doi.org\/10.3390\/ijms25094686","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,25]]}}}