{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T01:57:33Z","timestamp":1760234253440,"version":"build-2065373602"},"reference-count":22,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,4,29]],"date-time":"2021-04-29T00:00:00Z","timestamp":1619654400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Genetic testing in Brugada syndrome (BrS) is still not considered to be useful for clinical management of patients in the majority of cases, due to the current lack of understanding about the effect of specific variants. Additionally, family history of sudden death is generally not considered useful for arrhythmic risk stratification. We sought to demonstrate the usefulness of genetic testing and family history in diagnosis and risk stratification. The family history was collected for a proband who presented with a personal history of aborted cardiac arrest and in whom a novel variant in the SCN5A gene was found. Living family members underwent ajmaline testing, electrophysiological study, and genetic testing to determine genotype-phenotype segregation, if any. Patch-clamp experiments on transfected human embryonic kidney 293 cells enabled the functional characterization of the SCN5A novel variant in vitro. In this study, we provide crucial human data on the novel heterozygous variant NM_198056.2:c.5000T&gt;A (p.Val1667Asp) in the SCN5A gene, and demonstrate its segregation with a severe form of BrS and multiple sudden deaths. Functional data revealed a loss of function of the protein affected by the variant. These results provide the first disease association with this variant and demonstrate the usefulness of genetic testing for diagnosis and risk stratification in certain patients. This study also demonstrates the usefulness of collecting the family history, which can assist in understanding the severity of the disease in certain situations and confirm the importance of the functional studies to distinguish between pathogenic mutations and harmless genetic variants.<\/jats:p>","DOI":"10.3390\/ijms22094700","type":"journal-article","created":{"date-parts":[[2021,4,29]],"date-time":"2021-04-29T04:30:11Z","timestamp":1619670611000},"page":"4700","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Novel SCN5A p.Val1667Asp Missense Variant Segregation and Characterization in a Family with Severe Brugada Syndrome and Multiple Sudden Deaths"],"prefix":"10.3390","volume":"22","author":[{"given":"Michelle M.","family":"Monasky","sequence":"first","affiliation":[{"name":"Arrhythmology Department, IRCCS Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emanuele","family":"Micaglio","sequence":"additional","affiliation":[{"name":"Arrhythmology Department, IRCCS Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giuseppe","family":"Ciconte","sequence":"additional","affiliation":[{"name":"Arrhythmology Department, IRCCS Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7411-9069","authenticated-orcid":false,"given":"Ilaria","family":"Rivolta","sequence":"additional","affiliation":[{"name":"School of Medicine and Surgery, University of Milano-Bicocca, 20126 Monza, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7564-5677","authenticated-orcid":false,"given":"Valeria","family":"Borrelli","sequence":"additional","affiliation":[{"name":"Arrhythmology Department, IRCCS Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Ghiroldi","sequence":"additional","affiliation":[{"name":"Laboratory of Stem Cells for Tissue Engineering, IRCCS Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1340-9767","authenticated-orcid":false,"given":"Sara","family":"D\u2019Imperio","sequence":"additional","affiliation":[{"name":"Arrhythmology Department, IRCCS Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Binda","sequence":"additional","affiliation":[{"name":"School of Medicine and Surgery, University of Milano-Bicocca, 20126 Monza, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dario","family":"Melgari","sequence":"additional","affiliation":[{"name":"Arrhythmology Department, IRCCS Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2826-3040","authenticated-orcid":false,"given":"Sara","family":"Benedetti","sequence":"additional","affiliation":[{"name":"Clinical Genomics\u2014SMEL, IRCCS San Raffaele Hospital, 20132 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Predrag","family":"Mitrovic","sequence":"additional","affiliation":[{"name":"Clinical Center of Serbia, Department of Emergency Cardiology, Cardiology Clinic, School of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0712-2161","authenticated-orcid":false,"given":"Luigi","family":"Anastasia","sequence":"additional","affiliation":[{"name":"Laboratory of Stem Cells for Tissue Engineering, IRCCS Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy"},{"name":"Vita-Salute San Raffaele University, 20132 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valerio","family":"Mecarocci","sequence":"additional","affiliation":[{"name":"Arrhythmology Department, IRCCS Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"\u017darko","family":"\u0106alovi\u0107","sequence":"additional","affiliation":[{"name":"Arrhythmology Department, IRCCS Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giorgio","family":"Casari","sequence":"additional","affiliation":[{"name":"Clinical Genomics\u2014SMEL, IRCCS San Raffaele Hospital, 20132 Milan, Italy"},{"name":"Vita-Salute San Raffaele University, 20132 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlo","family":"Pappone","sequence":"additional","affiliation":[{"name":"Arrhythmology Department, IRCCS Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy"},{"name":"Vita-Salute San Raffaele University, 20132 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,29]]},"reference":[{"key":"ref_1","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 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