Priest James R, Ceresnak Scott R, Dewey Frederick E, Malloy-Walton Lindsey E, Dunn Kyla, Grove Megan E, Perez Marco V, Maeda Katsuhide, Dubin Anne M, Ashley Euan A
Division of Pediatric Cardiology, Stanford University School of Medicine, Stanford University, Stanford, California; Child Health Research Institute; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California.
Division of Cardiovascular Medicine; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California.
Heart Rhythm. 2014 Oct;11(10):1707-13. doi: 10.1016/j.hrthm.2014.06.030. Epub 2014 Jun 25.
The advent of clinical next generation sequencing is rapidly changing the landscape of rare disease medicine. Molecular diagnosis of long QT syndrome (LQTS) can affect clinical management, including risk stratification and selection of pharmacotherapy on the basis of the type of ion channel affected, but results from the current gene panel testing requires 4-16 weeks before return to clinicians.
A term female infant presented with 2:1 atrioventricular block and ventricular arrhythmias consistent with perinatal LQTS, requiring aggressive treatment including epicardial pacemaker and cardioverter-defibrillator implantation and sympathectomy on day of life 2. We sought to provide a rapid molecular diagnosis for the optimization of treatment strategies.
We performed Clinical Laboratory Improvement Amendments-certified rapid whole genome sequencing (WGS) with a speed-optimized bioinformatics platform to achieve molecular diagnosis at 10 days of life.
We detected a known pathogenic variant in KCNH2 that was demonstrated to be paternally inherited by follow-up genotyping. The unbiased assessment of the entire catalog of human genes provided by WGS revealed a maternally inherited variant of unknown significance in a novel gene.
Rapid clinical WGS provides faster and more comprehensive diagnostic information at 10 days of life than does standard gene panel testing. In selected clinical scenarios such as perinatal LQTS, rapid WGS can provide more timely and clinically actionable information than can a standard commercial test.
临床下一代测序技术的出现正在迅速改变罕见病医学的格局。长QT综合征（LQTS）的分子诊断可影响临床管理，包括风险分层以及根据受影响的离子通道类型选择药物治疗，但目前基因检测板检测的结果需要4至16周才能反馈给临床医生。
一名足月女婴出现2:1房室传导阻滞和与围产期LQTS一致的室性心律失常，在出生第2天需要积极治疗，包括植入心外膜起搏器和心脏复律除颤器以及进行交感神经切除术。我们试图提供快速分子诊断以优化治疗策略。
我们使用经过临床实验室改进修正案认证的快速全基因组测序（WGS）以及速度优化的生物信息学平台，在出生10天时实现分子诊断。
我们在KCNH2基因中检测到一个已知的致病变异，后续基因分型显示该变异为父系遗传。WGS对人类基因全目录的无偏评估揭示了一个在新基因中母系遗传的意义未明的变异。
与标准基因检测板检测相比，快速临床WGS在出生10天时能提供更快、更全面的诊断信息。在围产期LQTS等特定临床场景中，快速WGS能比标准商业检测提供更及时且具有临床可操作性的信息。
