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


METHODS
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.
Sebastian
S
Fröhler
Moritz
M
Kieslich
Claudia
C
Langnick
Mirjam
M
Feldkamp
Bernd
B
Opgen-Rhein
Felix
F
Berger
Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str, 10, Berlin 13125, Germany. Achim.Will@charite.de.
Joachim C
JC
Will
Wei
W
Chen
D001321:Autistic Disorder; D020746:Calcium Channels, L-Type / Q000235:genetics; D019295:Computational Biology; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008133:Long QT Syndrome / Q000175:diagnosis* / Q000235:genetics*; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D015203:Reproducibility of Results; D035781:Siblings; D013576:Syndactyly / Q000175:diagnosis* / Q000235:genetics*
C079146:CACNA1C protein, human; D020746:Calcium Channels, L-Type