title: Timothy syndrome 1 genotype without syndactyly and major extracardiac manifestations.
abstract: Timothy syndrome 1 (TS1) is a rare genetic disorder characterized by multisystem abnormalities including QT prolongation, congenital heart defects, facial dysmorphism, episodic hypoglycemia, and neurological symptoms. A morphological hallmark of TS1 is syndactyly, present in all cases. TS1 is caused by the canonical p.Gly406Arg mutation in the alternatively spliced exon 8A in the CACNA1C gene, encoding for the main cardiac L-type calcium channel. A variant case of TS1 is reported. The proband had intermittent fetal bradycardia with heart rate of 72 bpm. On the first day of life bradycardia due to 2:1 atrioventricular (AV) block and marked QTc prolongation of 600 ms was noted. On medical therapy with propranolol and mexiletine 1:1 AV conduction returned with QTc prolongation of 470-580 ms. The patient lacked other extracardiac manifestations, most importantly syndactyly, neurological complications or autism. On genetic analysis, the canonical TS1 causing mutation, p.Gly406Arg in exon 8A of the CACNA1C gene was detected. The CACNA1C p.Gly406Arg variant was not present in the parents, but was detected in different DNA samples of the index patient. Our case highlight further phenotypic variability in TS. Most importantly, it underlines that the lack of syndactyly does not exclude the presence of a TS1 genotype. © 2017 Wiley Periodicals, Inc.
authors.affiliation: Second Department of Internal Medicine and Cardiology Center, University of Szeged, Szeged, Hungary.
authors.forename: Róbert
authors.initials: R
authors.lastname: Sepp
authors.affiliation: Second Department of Internal Medicine and Cardiology Center, University of Szeged, Szeged, Hungary.
authors.forename: Lidia
authors.initials: L
authors.lastname: Hategan
authors.affiliation: Fejér County "Szent György" University Teaching Hospital, Székesfehérvár, Hungary.
authors.forename: Attila
authors.initials: A
authors.lastname: Bácsi
authors.affiliation: Seqomics Biotechnology Ltd., Mórahalom, Hungary.
authors.forename: Judit
authors.initials: J
authors.lastname: Cseklye
authors.affiliation: "Gottsegen György" National Institute of Cardiology, Budapest, Hungary.
authors.forename: László
authors.initials: L
authors.lastname: Környei
authors.affiliation: Second Department of Internal Medicine and Cardiology Center, University of Szeged, Szeged, Hungary.
authors.forename: János
authors.initials: J
authors.lastname: Borbás
authors.affiliation: Department of Medical Genetics, University of Szeged, Szeged, Hungary.
authors.forename: Márta
authors.initials: M
authors.lastname: Széll
authors.affiliation: Second Department of Internal Medicine and Cardiology Center, University of Szeged, Szeged, Hungary.
authors.forename: Tamás
authors.initials: T
authors.lastname: Forster
authors.affiliation: Seqomics Biotechnology Ltd., Mórahalom, Hungary.|Institute of Biochemistry, Biological Research Centre, Szeged, Hungary.
authors.forename: István
authors.initials: I
authors.lastname: Nagy
authors.affiliation: Institute of Biophysics, Biological Research Centre, Szeged, Hungary.|Department of Biochemistry and Medical Chemistry, University of Pécs, Pécs, Hungary.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Hegedűs
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution; D001321:Autistic Disorder / Q000175:diagnosis* / Q000235:genetics*; D015415:Biomarkers; D020746:Calcium Channels, L-Type / Q000235:genetics*; D004252:DNA Mutational Analysis; D004452:Echocardiography; D004562:Electrocardiography; D005091:Exons; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D007231:Infant, Newborn; D008133:Long QT Syndrome / Q000175:diagnosis* / Q000235:genetics*; D008297:Male; D009154:Mutation; D010641:Phenotype; D013576:Syndactyly / Q000175:diagnosis* / Q000235:genetics*
chemical_list: D015415:Biomarkers; C079146:CACNA1C protein, human; D020746:Calcium Channels, L-Type
keywords: AV block; CACNA1C gene; QTc prolongation; Timothy syndrome; syndactyly