title: Molecular diagnosis of long QT syndrome at 10 days of life by rapid whole genome sequencing.
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.
  
  
  CONCLUSIONS
  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.
authors: 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.
authors: James R
authors: JR
authors: Priest
authors: 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.
authors: Scott R
authors: SR
authors: Ceresnak
authors: Division of Cardiovascular Medicine; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California.
authors: Frederick E
authors: FE
authors: Dewey
authors: 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.
authors: Lindsey E
authors: LE
authors: Malloy-Walton
authors: Children's Heart Center, Lucile Packard Children's Hospital at Stanford, Palo Alto, California; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California.
authors: Kyla
authors: K
authors: Dunn
authors: Division of Cardiovascular Medicine; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California.
authors: Megan E
authors: ME
authors: Grove
authors: Division of Cardiovascular Medicine; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California.
authors: Marco V
authors: MV
authors: Perez
authors: Division of Cardiothoracic Surgery; Child Health Research Institute; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California.
authors: Katsuhide
authors: K
authors: Maeda
authors: Division of Pediatric Cardiology, Stanford University School of Medicine, Stanford University, Stanford, California; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California.
authors: Anne M
authors: AM
authors: Dubin
authors: Division of Cardiovascular Medicine; Child Health Research Institute; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California. Electronic address: euan@stanford.edu.
authors: Euan A
authors: EA
authors: Ashley
mesh_terms: D004247:DNA / Q000235:genetics*; D016757:Death, Sudden, Cardiac; D017147:Defibrillators, Implantable; D003937:Diagnosis, Differential; D004562:Electrocardiography; D005260:Female; D005500:Follow-Up Studies; D005819:Genetic Markers; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007231:Infant, Newborn; D008133:Long QT Syndrome / Q000175:diagnosis* / Q000235:genetics / Q000628:therapy; D025202:Molecular Diagnostic Techniques / Q000379:methods*; D009154:Mutation; D013997:Time Factors
chemical_list: D005819:Genetic Markers; D004247:DNA
keywords: Genetics; Genomics; Long QT syndrome; Pediatrics; Perinatal; Whole genome sequencing