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Am J Med Genet A. 2017 Mar;173(3):784-789. doi: 10.1002/ajmg.a.38084.

Timothy syndrome 1 genotype without syndactyly and major extracardiac manifestations.

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Second Department of Internal Medicine and Cardiology Center, University of Szeged, Szeged, Hungary.
Fejér County "Szent György" University Teaching Hospital, Székesfehérvár, Hungary.
Seqomics Biotechnology Ltd., Mórahalom, Hungary.
"Gottsegen György" National Institute of Cardiology, Budapest, Hungary.
Department of Medical Genetics, University of Szeged, Szeged, Hungary.
Institute of Biochemistry, Biological Research Centre, Szeged, Hungary.
Institute of Biophysics, Biological Research Centre, Szeged, Hungary.
Department of Biochemistry and Medical Chemistry, University of Pécs, Pécs, Hungary.


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.


AV block; CACNA1C gene; QTc prolongation; Timothy syndrome; syndactyly

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