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

Abstract

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.

Figure 1

Pedigree and validation results for the causative CACNA1C G402S mutation. (a) Pedigree of the Lebanese family. Blackened symbols indicate the affected individuals. (b) Sanger sequencing traces validating the CACNA1C c.1204G > A mutation in both affected children as well as the mosaic mutation in the father. (c) Restriction assay using enzyme DdeI, specifically cleaving PCR amplicons carrying the c.1204G > A mutation. A clear restriction pattern was found for both affected children, no restriction pattern was found for the apparently healthy mother and a mosaic restriction pattern was found for the father.