{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T14:56:25Z","timestamp":1781016985450,"version":"3.54.1"},"reference-count":38,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,2,8]],"date-time":"2023-02-08T00:00:00Z","timestamp":1675814400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Brugada syndrome (BrS) is an inherited primary channelopathy syndrome associated to sudden cardiac death. Overall, variants have been identified in eighteen genes encoding for ion channel subunits and seven genes for regulatory proteins. Recently, a missense variant in DLG1 has been found within a BrS phenotype-positive patient. DLG1 encodes for synapse associated protein 97 (SAP97), a protein characterized by the presence of multiple domains for protein\u2013protein interactions including PDZ domains. In cardiomyocytes, SAP97 interacts with Nav1.5, a PDZ binding motif of SCN5A and others potassium channel subunits. Aim of the Study: To characterize the phenotype of an Italian family with BrS syndrome carrying a DLG1 variant. Methods: Clinical and genetic investigations were performed. Genetic testing was performed with whole-exome sequencing (WES) using the Illumina platform. According to the standard protocol, a variant found by WES was confirmed in all members of the family by bi-directional capillary Sanger resequencing. The effect of the variant was investigated by using in silico prediction of pathogenicity. Results: The index case was a 74-year-old man with spontaneous type 1 BrS ECG pattern that experienced syncope and underwent ICD implantation. WES of the index case, performed assuming a dominant mode of inheritance, identified a heterozygous variant, c.1556G&gt;A (p.R519H), in the exon 15 of the DLG1 gene. In the pedigree investigation, 6 out of 12 family members had the variant. Carriers of the gene variant all had BrS ECG type 1 drug induced and showed heterogeneous cardiac phenotypes with two patients experiencing syncope during exercise and fever, respectively. The amino acid residue #519 lies near a PDZ domain and in silico analysis suggested a causal role for the variant. Modelling of the resulting protein structure predicted that the variant disrupts an H-bond and a likelihood of being pathogenic. As a consequence, it is likely that a conformational change affects protein functionality and the modulating role on ion channels. Conclusions: A DLG1 gene variant identified was associated with BrS. The variant could modify the formation of multichannel protein complexes, affecting ion channels to specific compartments in cardiomyocytes.<\/jats:p>","DOI":"10.3390\/genes14020427","type":"journal-article","created":{"date-parts":[[2023,2,8]],"date-time":"2023-02-08T03:57:16Z","timestamp":1675828636000},"page":"427","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["A Novel DLG1 Variant in a Family with Brugada Syndrome: Clinical Characteristics and In Silico Analysis"],"prefix":"10.3390","volume":"14","author":[{"given":"Maria","family":"d\u2019Apolito","sequence":"first","affiliation":[{"name":"Medical Genetics, Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9909-6513","authenticated-orcid":false,"given":"Francesco","family":"Santoro","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy"},{"name":"Cardiology Unit, Polyclinic Hospital of Foggia, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa","family":"Santacroce","sequence":"additional","affiliation":[{"name":"Medical Genetics, Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgia","family":"Cordisco","sequence":"additional","affiliation":[{"name":"Medical Genetics, Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9417-5909","authenticated-orcid":false,"given":"Ilaria","family":"Ragnatela","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Girolamo","family":"D\u2019Arienzo","sequence":"additional","affiliation":[{"name":"Cardiology Unit, Polyclinic Hospital of Foggia, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pier Luigi","family":"Pellegrino","sequence":"additional","affiliation":[{"name":"Cardiology Unit, Polyclinic Hospital of Foggia, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natale Daniele","family":"Brunetti","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy"},{"name":"Cardiology Unit, Polyclinic Hospital of Foggia, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurizio","family":"Margaglione","sequence":"additional","affiliation":[{"name":"Medical Genetics, Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"637","DOI":"10.2169\/internalmedicine.35.637","article-title":"Familial Occurrence of Electrocardiographic Abnormalities of the Brugada-Type","volume":"35","author":"Kobayashi","year":"1996","journal-title":"Intern. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1016\/j.jacc.2018.06.037","article-title":"Present Status of Brugada Syndrome JACC State-of-the-Art Review","volume":"72","author":"Brugada","year":"2018","journal-title":"JACC"},{"key":"ref_3","unstructured":"ESC Scientific Document Group (2022). 2022 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur. Heart J., 43, 3997\u20134126."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1016\/j.yjmcc.2010.07.012","article-title":"The pathophysiological mechanism underlying Brugada syndrome: Depolarization versus repolarization","volume":"49","author":"Wilde","year":"2010","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1111\/apha.12694","article-title":"Depolarization vs. repolarization: What is the mechanism of ventricular arrhythmogenesis underlying sodium channel haploinsufficiency in mouse hearts?","volume":"218","author":"Tse","year":"2016","journal-title":"Acta Physiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1161\/CIRCEP.108.789081","article-title":"Cardiac Ion Channels","volume":"2","author":"Grant","year":"2009","journal-title":"Circ. Arrhythmia Electrophysiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1038\/gim.2015.35","article-title":"Brugada syndrome: Clinical and genetic findings","volume":"18","author":"Campuzano","year":"2016","journal-title":"Genet. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"9","DOI":"10.3389\/fcvm.2016.00009","article-title":"The Brugada Syndrome: A Rare Arrhythmia Disorder with Complex Inheritance","volume":"3","author":"Gourraud","year":"2016","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1161\/CIRCGENETICS.109.853374","article-title":"SCN5A Mutations and the Role of Genetic Background in the Pathophysiology of Brugada Syndrome","volume":"2","author":"Probst","year":"2009","journal-title":"Circ. Cardiovasc. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1161\/CIRCGENETICS.109.921940","article-title":"Nature\u2019s Genetic Gradients and the Clinical Phenotype","volume":"2","author":"Marian","year":"2009","journal-title":"Circ. Cardiovasc. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1161\/CIRCULATIONAHA.118.035070","article-title":"Reappraisal of reported genes for sudden arrhythmic death","volume":"138","author":"Hosseini","year":"2018","journal-title":"Circulation"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.hrthm.2009.09.069","article-title":"An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing","volume":"7","author":"Kapplinger","year":"2010","journal-title":"Heart Rhythm"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Di Resta, C., Berg, J., Villatore, A., Maia, M., Pili, G., Fioravanti, F., Tomaiuolo, R., Sala, S., Benedetti, S., and Peretto, G. (2022). Concealed Substrates in Brugada Syndrome: Isolated Channelopathy or Associated Cardiomyopathy?. Genes, 13.","DOI":"10.3390\/genes13101755"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"808","DOI":"10.3389\/fphys.2017.00808","article-title":"Ion channel trafficking: Control of ion channel density as a target for arrhythmias?","volume":"8","author":"Balse","year":"2017","journal-title":"Front. Physiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1016\/j.bbamem.2013.03.015","article-title":"The anchoring protein SAP97 influences the trafficking and localisation of multiple membrane channels","volume":"1838","author":"Fourie","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"H1851","DOI":"10.1152\/ajpheart.01045.2007","article-title":"The anchoring protein SAP97 retains Kv1.5 channels in the plasma membrane of cardiac myocytes","volume":"294","author":"Balse","year":"2008","journal-title":"Am. J. Physiol. Circ. Physiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1016\/S0008-6363(02)00602-8","article-title":"Expression, regulation and role of the MAGUK protein SAP-97 in human atrial myocardium","volume":"56","author":"Godreau","year":"2002","journal-title":"Cardiovasc. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1161\/CIRCRESAHA.108.191007","article-title":"Kv4 Potassium Channels Form a Tripartite Complex With the Anchoring Protein SAP97 and CaMKII in Cardiac Myocytes","volume":"104","author":"Balse","year":"2009","journal-title":"Circ. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.hrthm.2014.09.057","article-title":"Cardiac Specific Ablation of Synapse-Associated Protein SAP97 in Mice Decreases Potassium Currents but Not Sodium Current","volume":"12","author":"Gillet","year":"2015","journal-title":"Heart Rhythm"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1242\/jcs.114.5.987","article-title":"Inward rectifier potassium channel Kir2.2 is associated with synapse-associated protein SAP97","volume":"114","author":"Leonoudakis","year":"2001","journal-title":"J. Cell Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"E2134","DOI":"10.1073\/pnas.1109370109","article-title":"Dynamic reciprocity of sodium and potassium channel expression in a macromolecular complex controls cardiac excitability and arrhythmia","volume":"109","author":"Milstein","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1093\/cvr\/cvw009","article-title":"Nav1.5 N-terminal Domain Binding to A1-Syntrophin Increases Membrane Density of Human Kir2.1, Kir2.2 and Nav1.5 Channels","volume":"110","author":"Matamoros","year":"2016","journal-title":"Cardiovasc. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1161\/CIRCRESAHA.110.228312","article-title":"SAP97 and Dystrophin Macromolecular Complexes Determine Two Pools of Cardiac Sodium Channels Nav1.5 in Cardiomyocytes","volume":"108","author":"Petitprez","year":"2011","journal-title":"Circ. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"28000","DOI":"10.1074\/jbc.M110.110858","article-title":"Regulation of Cardiac Inward Rectifier Potassium Current (IK1) by Synapse-associated Protein-97","volume":"285","author":"Vaidyanathan","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"H1357","DOI":"10.1152\/ajpheart.00481.2019","article-title":"Abnormal myocardial expression of SAP97 is associated with arrhythmogenic risk","volume":"318","author":"Musa","year":"2020","journal-title":"Am. J. Physiol. Circ. Physiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2514","DOI":"10.1161\/01.CIR.0000034169.45752.4A","article-title":"Study Group on the Molecular Basis of Arrhythmias of the European Society of Cardiology Proposed diagnostic criteria for the Brugada syndrome: Consensus report","volume":"106","author":"Wilde","year":"2002","journal-title":"Circulation"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1442","DOI":"10.1016\/j.hrthm.2017.06.031","article-title":"Sodium-channel blocker challenge in the familial screening of Brugada syndrome: Safety and predictors of positivity","volume":"14","author":"Therasse","year":"2017","journal-title":"Heart Rhythm"},{"key":"ref_28","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":"Sue","year":"2015","journal-title":"Genet. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2989","DOI":"10.1111\/all.14454","article-title":"A myoferlin gain-of-function variant associates with a new type of hereditary angioedema","volume":"75","author":"Ariano","year":"2020","journal-title":"Allergy"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1034","DOI":"10.1055\/s-0037-1613129","article-title":"Glanzmann\u2019s Thrombasthenia: Identification of 19 New Mutations in 30 Patients","volume":"87","author":"Colaizzo","year":"2002","journal-title":"Thromb. Haemost."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1016\/S0140-6736(99)05277-0","article-title":"Brugada syndrome and sudden cardiac death in children","volume":"355","author":"Priori","year":"2000","journal-title":"Lancet"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1038\/ng.2712","article-title":"Common variants at SCN5A-SCN10A and HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death","volume":"45","author":"Bezzina","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Monasky, M.M., Micaglio, E., Ciconte, G., and Pappone, C. (2020). Brugada syndrome: Oligogenic or mendelian disease?. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21051687"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1016\/j.hrthm.2011.02.021","article-title":"Transient outward current (I(to)) gain-of-function mutations in the KCND3-encoded Kv4.3 potassium channel and Brugada syndrome","volume":"8","author":"Giudicessi","year":"2011","journal-title":"Heart Rhythm"},{"key":"ref_35","first-page":"319","article-title":"Potassium-channel mutations and cardiac arrhythmias--diagnosis and therapy","volume":"9","author":"Giudicessi","year":"2012","journal-title":"Rev. Cardiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1161\/CIRCGENETICS.110.959130","article-title":"MOG1: A new susceptibility gene for Brugada syndrome","volume":"4","author":"Kattygnarath","year":"2011","journal-title":"Circ. Cardiovasc. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"ehx493","DOI":"10.1093\/eurheartj\/ehx493.P6281","article-title":"P6281A DLG1 polymorphism shortens the action potential duration and the QT interval","volume":"38","author":"Delpon","year":"2017","journal-title":"Eur. Heart J."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"10707","DOI":"10.1038\/s41598-020-67109-z","article-title":"The p.P888L SAP97 polymorphism increases the transient outward current (Ito,f) and abbreviates the action potential duration and the QT interval","volume":"10","author":"Tinaquero","year":"2020","journal-title":"Sci. Rep."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/2\/427\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:27:34Z","timestamp":1760120854000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/2\/427"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,8]]},"references-count":38,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["genes14020427"],"URL":"https:\/\/doi.org\/10.3390\/genes14020427","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,8]]}}}