title: SCN4A variants and Brugada syndrome: phenotypic and genotypic overlap between cardiac and skeletal muscle sodium channelopathies.
abstract: SCN5A mutations involving the α-subunit of the cardiac voltage-gated muscle sodium channel (NaV1.5) result in different cardiac channelopathies with an autosomal-dominant inheritance such as Brugada syndrome. On the other hand, mutations in SCN4A encoding the α-subunit of the skeletal voltage-gated sodium channel (NaV1.4) cause non-dystrophic myotonia and/or periodic paralysis. In this study, we investigated whether cardiac arrhythmias or channelopathies such as Brugada syndrome can be part of the clinical phenotype associated with SCN4A variants and whether patients with Brugada syndrome present with non-dystrophic myotonia or periodic paralysis and related gene mutations. We therefore screened seven families with different SCN4A variants and non-dystrophic myotonia phenotypes for Brugada syndrome and performed a neurological, neurophysiological and genetic work-up in 107 Brugada families. In the families with an SCN4A-associated non-dystrophic myotonia, three patients had a clinical diagnosis of Brugada syndrome, whereas we found a remarkably high prevalence of myotonic features involving different genes in the families with Brugada syndrome. One Brugada family carried an SCN4A variant that is predicted to probably affect function, one family suffered from a not genetically confirmed non-dystrophic myotonia, one family was diagnosed with myotonic dystrophy (DMPK gene) and one family had a Thomsen disease myotonia congenita (CLCN1 variant that affects function). Our findings and data suggest a possible involvement of SCN4A variants in the pathophysiological mechanism underlying the development of a spontaneous or drug-induced type 1 electrocardiographic pattern and the occurrence of malignant arrhythmias in some patients with Brugada syndrome.
authors.affiliation: Department of Neurology, Center for Neurosciences, UZ Brussel, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
authors.forename: Véronique
authors.initials: V
authors.lastname: Bissay
authors.affiliation: Department of Cardiology, Heart Rhythm Management Center, UZ Brussel, Vrije Universiteit Brussel (VUB), Brussels, Belgium.|Department of Electrophysiology, Thorax Center, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Sophie C H
authors.initials: SC
authors.lastname: Van Malderen
authors.affiliation: Center for Medical Genetics, Reproduction and Genetics; Genetics and Regenerative Medicine, UZ Brussel, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
authors.forename: Kathelijn
authors.initials: K
authors.lastname: Keymolen
authors.affiliation: Center for Medical Genetics, Reproduction and Genetics; Genetics and Regenerative Medicine, UZ Brussel, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
authors.forename: Willy
authors.initials: W
authors.lastname: Lissens
authors.affiliation: Center for Medical Genetics, Reproduction and Genetics; Genetics and Regenerative Medicine, UZ Brussel, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
authors.forename: Uschi
authors.initials: U
authors.lastname: Peeters
authors.affiliation: Center for Medical Genetics, Reproduction and Genetics; Genetics and Regenerative Medicine, UZ Brussel, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
authors.forename: Dorien
authors.initials: D
authors.lastname: Daneels
authors.affiliation: Pediatric Neurology Unit, Department of Pediatrics, UZ Brussel, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Jansen
authors.affiliation: Department of Cardiology, Heart Rhythm Management Center, UZ Brussel, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Pappaert
authors.affiliation: Department of Cardiology, Heart Rhythm Management Center, UZ Brussel, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
authors.forename: Pedro
authors.initials: P
authors.lastname: Brugada
authors.affiliation: Department of Neurology, Center for Neurosciences, UZ Brussel, Vrije Universiteit Brussel (VUB), Brussels, Belgium.|Department of Neurology, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Jacques
authors.initials: J
authors.lastname: De Keyser
authors.affiliation: Center for Medical Genetics, Reproduction and Genetics; Genetics and Regenerative Medicine, UZ Brussel, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
authors.forename: Sonia
authors.initials: S
authors.lastname: Van Dooren
mesh_terms: D000328:Adult; D000368:Aged; D053840:Brugada Syndrome / Q000000981:diagnostic imaging / Q000235:genetics*; D053447:Channelopathies / Q000235:genetics*; D004562:Electrocardiography; D004576:Electromyography; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006801:Humans; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000473:pathology*; D009154:Mutation / Q000235:genetics*; D009206:Myocardium / Q000473:pathology*; D062553:NAV1.4 Voltage-Gated Sodium Channel / Q000235:genetics*; D010641:Phenotype; D014463:Ultrasonography
chemical_list: D062553:NAV1.4 Voltage-Gated Sodium Channel; C106251:SCN4A protein, human