title: Expanding the phenotype of Timothy syndrome type 2: an adolescent with ventricular fibrillation but normal development.
abstract: Timothy syndrome is a rare multiorgan disorder with prolonged QTc interval, congenital heart defects, syndactyly, typical facial features and neurodevelopmental problems. Ventricular tachyarrhythmia is the leading cause of death at early age. Classical Timothy syndrome type 1 (TS1) results from a recurrent de novo CACNA1C mutation, G406R in exon 8 A. An atypical form of Timothy syndrome type 2 (TS2) is caused by mutations in G406R and G402S in the alternatively spliced exon 8. Only one individual for each exon 8 mutations has been described. In contrast to multiorgan disease caused by the mutation in G406R either in exon 8 A or 8, the G402S carrier manifested only an isolated cardiac phenotype with LQTS and cardiac arrest. We describe a teenage patient resuscitated from ventricular fibrillation and treated with an implantable cardioverter defibrillator. She has no other organ manifestations, no syndactyly, normal neurodevelopment and her QTc has ranged between 440-480 ms. There is no family history of arrhythmias or sudden death. Targeted oligonucleotide-selective sequencing (OS-Seq) of channelopathy genes revealed a de novo substitution, G402S in exon 8 of CACNA1C. Direct sequencing of blood and saliva derived DNA showed an identical mutation peak suggesting ubiquitous expression in different tissues. The phenotype of our patient and the previously described patient show an isolated arrhythmia disease with no other organ manifestations of classical Timothy syndrome.
authors.affiliation: Children's Hospital Helsinki, Pediatric Cardiology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Anita
authors.initials: A
authors.lastname: Hiippala
authors.forename: Jonna
authors.initials: J
authors.lastname: Tallila
authors.forename: Samuel
authors.initials: S
authors.lastname: Myllykangas
authors.forename: Juha W
authors.initials: JW
authors.lastname: Koskenvuo
authors.forename: Tero-Pekka
authors.initials: TP
authors.lastname: Alastalo
mesh_terms: D000293:Adolescent; D001321:Autistic Disorder / Q000175:diagnosis* / Q000235:genetics; D020746:Calcium Channels, L-Type / Q000235:genetics; D004562:Electrocardiography; D005260:Female; D056726:Genetic Association Studies; D055106:Genome-Wide Association Study; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008133:Long QT Syndrome / Q000175:diagnosis* / Q000235:genetics; D009154:Mutation; D010641:Phenotype; D051191:Plakophilins / Q000235:genetics; D013576:Syndactyly / Q000175:diagnosis* / Q000235:genetics; D014693:Ventricular Fibrillation / Q000175:diagnosis / Q000235:genetics; D051178:alpha Catenin / Q000235:genetics
chemical_list: C079146:CACNA1C protein, human; C441963:CTNNA3 protein, human; D020746:Calcium Channels, L-Type; C495337:PKP2 protein, human; D051191:Plakophilins; D051178:alpha Catenin
keywords: CACNA1C; OS-Seq; Timothy syndrome; channelopathies; genetics; idiopathic ventricular fibrillation; long QT syndrome