Timothy syndrome (TS), characterised by multiple system malfunction especially the prolonged corrected QT interval and synchronised appearance of hand/foot syndactyly, is an extremely rare disease affecting early life with devastating arrhythmia. In this work, firstly, the various mutations in causative gene CACNA1C encoding cardiac L-type voltage-gated calcium channel (LTCC), regard with the genetic pathogeny and nomenclature of TS are reviewed. Secondly, the expression profile and function of CACNA1C gene encoding Cav1.2 proteins, and its gain-of-function mutation in TS leading to multiple organ disease phenotypes especially arrhythmia are discussed. More importantly, we focus on the altered molecular mechanism underlying arrhythmia in TS, and discuss about how LTCC malfunction in TS can cause disorganised calcium handling with excessive intracellular calcium and its triggered dysregulated excitation–transcription coupling. In addition, current therapeutics for TS cardiac phenotypes including LTCC blockers, beta-adrenergic blocking agents, sodium channel blocker, multichannel inhibitors and pacemakers are summarised. Eventually, the research strategy using patient-specific induced pluripotent stem cells is recommended as one of the promising future directions for developing therapeutic approaches. This review updates our understanding on the research progress and future avenues to study the genetics and molecular mechanism underlying the pathogenesis of devastating arrhythmia within TS, and provides novel insights for developing therapeutic measures.

蒂莫西综合征 (TS) 的特点是多系统功能障碍，尤其是校正 QT 间期延长和手/足并指同步出现，是一种极其罕见的疾病，影响早期生命，并伴有严重的心律失常。本工作首先对编码心脏L型电压门控钙通道(LTCC)的致病基因CACNA1C的各种突变以及TS的遗传发病机制和命名进行了综述。其次，讨论了编码 Ca v 1.2 蛋白的CACNA1C基因的表达谱和功能，及其在 TS 中导致多器官疾病表型尤其是心律失常的功能获得性突变。更重要的是，我们关注 TS 中心律失常的分子机制改变，并讨论 TS 中的 LTCC 故障如何导致细胞内钙过多而导致钙处理紊乱及其引发的兴奋转录耦合失调。此外，还总结了当前 TS 心脏表型的治疗方法，包括 LTCC 阻滞剂、β-肾上腺素能阻滞剂、钠通道阻滞剂、多通道抑制剂和起搏器。最终，使用患者特异性诱导多能干细胞的研究策略被推荐为开发治疗方法的有前途的未来方向之一。这篇综述更新了我们对 TS 破坏性心律失常发病机制的遗传学和分子机制的研究进展和未来途径的理解，并为制定治疗措施提供了新的见解。