Boczek Nicole J, Miller Erin M, Ye Dan, Nesterenko Vladislav V, Tester David J, Antzelevitch Charles, Czosek Richard J, Ackerman Michael J, Ware Stephanie M
Center for Clinical and Translational Science, Mayo Clinic, Rochester, Minnesota; Mayo Graduate School, Mayo Clinic, Rochester, Minnesota.
The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Heart Rhythm. 2015 Jan;12(1):211-9. doi: 10.1016/j.hrthm.2014.09.051. Epub 2014 Sep 28.
Timothy syndrome (TS) is a rare multisystem genetic disorder characterized by a myriad of abnormalities, including QT prolongation, syndactyly, and neurologic symptoms. The predominant genetic causes are recurrent de novo missense mutations in exon 8/8A of the CACNA1C-encoded L-type calcium channel; however, some cases remain genetically elusive.
The purpose of this study was to identify the genetic cause of TS in a patient who did not harbor a CACNA1C mutation in exon 8/A, and was negative for all other plausible genetic substrates.
Diagnostic exome sequencing was used to identify the genetic substrate responsible for our case of TS. The identified mutation was characterized using whole-cell patch-clamp technique, and the results of these analyses were modeled using a modified Luo-Rudy dynamic model to determine the effects on the cardiac action potential.
Whole exome sequencing revealed a novel CACNA1C mutation, p.Ile1166Thr, in a young male with diagnosed TS. Functional electrophysiologic analysis identified a novel mechanism of TS-mediated disease, with an overall loss of current density and a gain-of-function shift in activation, leading to an increased window current. Modeling studies of this variant predicted prolongation of the action potential as well as the development of spontaneous early afterdepolarizations.
Through expanded whole exome sequencing, we identified a novel genetic substrate for TS, p.Ile1166Thr-CACNA1C. Electrophysiologic experiments combined with modeling studies have identified a novel TS mechanism through increased window current. Therefore, expanded genetic testing in cases of TS to the entire CACNA1C coding region, if initial targeted testing is negative, may be warranted.
Timothy综合征（TS）是一种罕见的多系统遗传性疾病，其特征是存在众多异常，包括QT间期延长、并指畸形和神经症状。主要的遗传原因是编码L型钙通道的CACNA1C基因外显子8/8A中反复出现的新生错义突变；然而，一些病例的遗传原因仍然不明。
本研究旨在确定一名外显子8/A中未携带CACNA1C突变且所有其他可能的遗传底物检测均为阴性的TS患者的遗传病因。
采用诊断性外显子组测序来确定导致我们这位TS患者发病的遗传底物。使用全细胞膜片钳技术对鉴定出的突变进行特征分析，并使用改良的Luo-Rudy动态模型对这些分析结果进行建模，以确定其对心脏动作电位的影响。
全外显子组测序在一名诊断为TS的年轻男性中发现了一种新的CACNA1C突变，即p.Ile1166Thr。功能性电生理分析确定了TS介导疾病的一种新机制，即电流密度总体降低以及激活时功能获得性移位，导致窗电流增加。对该变体的建模研究预测动作电位延长以及自发早期后去极化的发生。
通过扩展全外显子组测序，我们确定了一种新的TS遗传底物，即p.Ile1166Thr-CACNA1C。电生理实验与建模研究相结合，通过增加窗电流确定了一种新的TS机制。因此，如果初始靶向检测为阴性，对TS病例扩展至整个CACNA1C编码区进行基因检测可能是必要的。
