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

BMC Medical Genetics

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

[1] Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str. 10, Berlin 13125, Germany;Division of Pediatric Cardiology, Charité University Hospital, Augustenburger Platz 1, Berlin 13353, Germany

关键词: LQTS;    Mosaic mutation;    Exome sequencing;    Timothy syndrome;   

Others  :  1091995
DOI  :  10.1186/1471-2350-15-48

 received in 2013-06-12, accepted in 2014-04-25,  发布年份 2014

【 摘 要 】

Background

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.

Conclusions

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.

【 授权许可】

   
2014 Fröhler et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

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