Abstract
BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.