{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,1]],"date-time":"2025-11-01T13:51:51Z","timestamp":1762005111110,"version":"3.40.5"},"reference-count":33,"publisher":"Cambridge University Press (CUP)","issue":"10","license":[{"start":{"date-parts":[[2019,9,3]],"date-time":"2019-09-03T00:00:00Z","timestamp":1567468800000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/www.cambridge.org\/core\/terms"}],"content-domain":{"domain":["cambridge.org"],"crossmark-restriction":true},"short-container-title":["Cardiol Young"],"published-print":{"date-parts":[[2019,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec id=\"S1047951119001860_as1\"><jats:title>Introduction:<\/jats:title><jats:p>The <jats:italic>SCN5A<\/jats:italic> gene is implicated in many arrhythmogenic and cardiomyopathic processes. We identified a novel <jats:italic>SCN5A<\/jats:italic> variant in a family with significant segregation in individuals affected with progressive sinus and atrioventricular nodal disease, atrial arrhythmia, dilated cardiomyopathy, and early sudden cardiac arrest.<\/jats:p><\/jats:sec><jats:sec id=\"S1047951119001860_as2\"><jats:title>Methods:<\/jats:title><jats:p>A patient pedigree was created following the clinical evaluation of three affected individuals, two monozygotic twins and a paternal half-brother, which lead to the evaluation of a paternal half-sister (four siblings with the same father and three mothers) all of whom experienced varying degrees of atrial arrhythmias, conduction disease, and dilated cardiomyopathy in addition to a paternal history of unexplained death in his 50s with similar autopsy findings. The index male underwent sequencing of 58 genes associated with cardiomyopathies. Sanger sequencing was used to provide data for bases with insufficient coverage and for bases in some known regions of genomic segmental duplications. All clinically significant and novel variants were confirmed by independent Sanger sequencing.<\/jats:p><\/jats:sec><jats:sec id=\"S1047951119001860_as3\"><jats:title>Results:<\/jats:title><jats:p>All relatives tested were shown to have the same <jats:italic>SCN5A<\/jats:italic> variant of unknown significance (p. Asp197His) and the monozygotic twins shared a co-occurring <jats:italic>NEXN<\/jats:italic> (p. Glu575*). Segregation analysis demonstrates likely pathogenic trait for the <jats:italic>SCN5A<\/jats:italic> variant with an additional possible role for the <jats:italic>NEXN<\/jats:italic> variant in combination.<\/jats:p><\/jats:sec><jats:sec id=\"S1047951119001860_as4\"><jats:title>Conclusions:<\/jats:title><jats:p>There is compelling clinical evidence suggesting that the <jats:italic>SCN5A<\/jats:italic> variant p. Asp197His may be re-classified as likely pathogenic based on the segregation analysis of our family of interest. Molecular mechanism studies are pending.<\/jats:p><\/jats:sec>","DOI":"10.1017\/s1047951119001860","type":"journal-article","created":{"date-parts":[[2019,9,3]],"date-time":"2019-09-03T07:36:27Z","timestamp":1567496187000},"page":"1257-1263","update-policy":"https:\/\/doi.org\/10.1017\/policypage","source":"Crossref","is-referenced-by-count":11,"title":["Clinical characterisation of a novel <i>SCN5A<\/i> variant associated with progressive malignant arrhythmia and dilated cardiomyopathy"],"prefix":"10.1017","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3966-4261","authenticated-orcid":false,"given":"Adam C.","family":"Kean","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin 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