Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str, 10, Berlin 13125, Germany.
BMC Med Genet. 2014 Apr 29;15:48. doi: 10.1186/1471-2350-15-48.
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.
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.
长 QT 综合征 (LQTS) 导致心电图 QT 间期延长，从而引发危及生命的心动过速和心室颤动。LQTS 的一种非典型形式，即 Timothy 综合征 (TS)，与并指、免疫缺陷、认知和神经异常以及明显的颅面异常有关。
在一个两个孩子都被诊断为临床 LQTS 的家庭中，我们进行了全外显子组测序，以全面筛选导致突变的原因，因为对长 QT 综合征靶基因的靶向候选基因 panel 筛选未能发现任何潜在的遗传缺陷。使用外显子组测序，我们在两个受影响的孩子中发现 CACNA1C 基因第 8 外显子的 p.402G > S 突变，这是一种电压依赖性 Ca2+通道。该突变是从他们的父亲那里遗传的，是一个镶嵌突变携带者。基于这一分子发现，并进行更仔细的临床检查，我们将诊断细化为 Timothy 综合征 (TS2)，从而能够提出新的治疗方法。
我们的研究强调了准确诊断罕见病患者，尤其是那些具有非典型临床表现的患者的困难。这种挑战可以通过全面和无偏的突变筛查来解决，如外显子组测序。
