Genetic testing has become standard of care for patients with long QT syndrome (LQTS), providing diagnostic, prognostic, and therapeutic information for both probands and their family members. However, up to a quarter of patients with LQTS do not have identifiable Mendelian pathogenic variants in the currently known LQTS-associated genes. This absence of genetic confirmation, intriguingly, does not lessen the severity of LQTS, with the prognosis in these gene-elusive patients with unequivocal LQTS mirroring genotype-positive patients in the limited data available. Such a conundrum instigates an exploration into the causes of corrected QT interval (QTc) prolongation in these cases, unveiling a broad spectrum of potential scenarios and mechanisms. These include multiple environmental influences on QTc prolongation, exercise-induced repolarization abnormalities, and the profound implications of the constantly evolving nature of genetic testing and variant interpretation. In addition, the rapid advances in genetics have the potential to uncover new causal genes, and polygenic risk factors may aid in the diagnosis of high-risk patients. Navigating this multifaceted landscape requires a systematic approach and expert knowledge, integrating the dynamic nature of genetics and patient-specific influences for accurate diagnosis, management, and counseling of patients. The role of a subspecialized expert cardiogenetic clinic is paramount in evaluation to navigate this complexity. Amid these intricate aspects, this review outlines potential causes of gene-elusive LQTS. It also provides an outline for the evaluation of patients with negative and inconclusive genetic test results and underscores the need for ongoing adaptation and reassessment in our understanding of LQTS, as the complexities of gene-elusive LQTS are increasingly deciphered.

中文翻译：

---

揭开基因难以捉摸的长 QT 综合征的复杂性

基因检测已成为长 QT 综合征 (LQTS) 患者的标准治疗，为先证者及其家庭成员提供诊断、预后和治疗信息。然而，多达四分之一的 LQTS 患者在目前已知的 LQTS 相关基因中不具有可识别的孟德尔致病变异。有趣的是，缺乏基因确认并不能减轻 LQTS 的严重程度，在有限的可用数据中，这些具有明确 LQTS 的基因难以捉摸的患者的预后与基因型阳性患者的预后相似。这一难题引发了对这些病例中校正 QT 间期 (QTc) 延长的原因的探索，揭示了广泛的潜在场景和机制。其中包括对 QTc 延长的多种环境影响、运动引起的复极异常，以及基因检测和变异解释不断发展的本质的深远影响。此外，遗传学的快速进步有可能发现新的致病基因，多基因危险因素可能有助于高危患者的诊断。驾驭这一多方面的景观需要系统的方法和专业知识，整合遗传学的动态性质和患者特定的影响，以对患者进行准确的诊断、管理和咨询。专科心脏遗传学专家诊所的作用对于应对这种复杂性的评估至关重要。在这些复杂的方面中，这篇综述概述了基因难以捉摸的 LQTS 的潜在原因。它还为评估基因检测结果为阴性和不确定的患者提供了大纲，并强调了我们对 LQTS 理解不断调整和重新评估的必要性，因为基因难以捉摸的 LQTS 的复杂性越来越被解读。