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Open Access Case report

Exome sequencing helped the fine diagnosis of two siblings afflicted with atypical Timothy syndrome (TS2)

Sebastian Fröhler1, Moritz Kieslich2, Claudia Langnick1, Mirjam Feldkamp1, Bernd Opgen-Rhein2, Felix Berger2, Joachim C Will2* and Wei Chen1*

Author Affiliations

1 Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str. 10, Berlin 13125, Germany

2 Division of Pediatric Cardiology, Charité University Hospital, Augustenburger Platz 1, Berlin 13353, Germany

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BMC Medical Genetics 2014, 15:48  doi:10.1186/1471-2350-15-48

Published: 29 April 2014



Long-QT syndrome (LQTS) causes a prolongation of the QT-interval in the ECG leading to life threatening tachyarrhythmia and ventricular fibrillation. One atypical form of LQTS, Timothy syndrome (TS), is associated with syndactyly, immune deficiency, cognitive and neurological abnormalities as well as distinct cranio-facial abnormalities.

Case presentation

On a family with both children diagnosed with clinical LQTS, we performed whole exome sequencing to comprehensively screen for causative mutations after a targeted candidate gene panel screen for Long-QT syndrome target genes failed to identify any underlying genetic defect. Using exome sequencing, we identified in both affected children, a p.402G > S mutation in exon 8 of the CACNA1C gene, a voltage-dependent Ca2+ channel. The mutation was inherited from their father, a mosaic mutation carrier. Based on this molecular finding and further more careful clinical examination, we refined the diagnosis to be Timothy syndrome (TS2) and thereby were able to present new therapeutic approaches.


Our study highlights the difficulties in accurate diagnosis of patients with rare diseases, especially those with atypical clinical manifestation. Such challenge could be addressed with the help of comprehensive and unbiased mutation screening, such as exome sequencing.

Timothy syndrome; Exome sequencing; Mosaic mutation; LQTS