Randomized Clinical Trial of First-Line Genome Sequencing in Pediatric White Matter Disorders

Adeline Vanderver; Geneviève Bernard; Guy Helman; Omar Sherbini; Ryan Boeck; Jeffrey Cohn; Abigail Collins; Scott Demarest; Katherine Dobbins; Lisa Emrick; Jamie L Fraser; Diane Masser-Frye; Jean Hayward; Swati Karmarkar; Stephanie Keller; Samuel Mirrop; Wendy Mitchell; Sheel Pathak; Elliott Sherr; Keith van Haren; Erica Waters; Jenny L Wilson; Leah Zhorne; Raphael Schiffmann; Marjo S van der Knaap; Amy Pizzino; Holly Dubbs; Justine Shults; Cas Simons; Ryan J Taft; LeukoSEQ Workgroup

doi:10.1002/ana.25757

Randomized Clinical Trial of First-Line Genome Sequencing in Pediatric White Matter Disorders

Ann Neurol. 2020 Aug;88(2):264-273. doi: 10.1002/ana.25757. Epub 2020 Jun 9.

Authors

Adeline Vanderver^{1

2}, Geneviève Bernard^{3

4

5}, Guy Helman^{6

7}, Omar Sherbini¹, Ryan Boeck^{8

9}, Jeffrey Cohn¹⁰, Abigail Collins¹¹, Scott Demarest¹¹, Katherine Dobbins¹², Lisa Emrick¹³, Jamie L Fraser^{14

15}, Diane Masser-Frye¹⁶, Jean Hayward¹⁷, Swati Karmarkar^{18

19}, Stephanie Keller²⁰, Samuel Mirrop²¹, Wendy Mitchell^{22

23}, Sheel Pathak^{24

25}, Elliott Sherr²⁶, Keith van Haren²⁷, Erica Waters²⁸, Jenny L Wilson²⁹, Leah Zhorne³⁰, Raphael Schiffmann³¹, Marjo S van der Knaap^{32

33}, Amy Pizzino¹, Holly Dubbs¹, Justine Shults³⁴, Cas Simons^{6

7}, Ryan J Taft³⁵; LeukoSEQ Workgroup

Affiliations

¹ Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
² Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
³ Departments of Neurology and Neurosurgery, Pediatrics, and Human Genetics, McGill University, Montreal, Quebec, Canada.
⁴ Department of Specialized Medicine, Division of Medical Genetics, Montreal Children's Hospital and McGill University Health Centre, Montreal, Quebec, Canada.
⁵ Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.
⁶ Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
⁷ Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia.
⁸ Child Neurology Consultants of Austin, Austin, Texas, USA.
⁹ University of Texas at Austin Dell Medical School, Austin, Texas, USA.
¹⁰ Family Medicine, Broadlands Family Practice at Ashburn, Ashburn, Virginia, USA.
¹¹ Department of Neurology, Anschutz Medical Campus, University of Colorado School of Medicine, Aurora, Colorado, USA.
¹² Walter Reed National Military Medical Center, Bethesda, Maryland, USA.
¹³ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
¹⁴ Division of Genetics and Metabolism, Rare Disease Institute, Children's National Hospital, Washington, District of Columbia, USA.
¹⁵ George Washington University, Washington, District of Columbia, USA.
¹⁶ Rady Children's Hospital, San Diego, California, USA.
¹⁷ Department of Pediatrics, Kaiser Oakland, Oakland, California, USA.
¹⁸ Department of Neurology, Le Bonheur Children's Hospital, Memphis, Tennessee, USA.
¹⁹ Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
²⁰ Division of Neurology, Department of Pediatrics, Emory University, Atlanta, Georgia, USA.
²¹ Pediatric Associates of Austin, Austin, Texas, USA.
²² Division of Neurology, Children's Hospital of Los Angeles, Los Angeles, California, USA.
²³ Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
²⁴ Clinical Neurology, Washington University Clinical Associates, St Louis, Missouri, USA.
²⁵ Department of Neurology, Washington University School of Medicine, St Louis, Missouri, USA.
²⁶ Department of Neurology, University of California, San Francisco School of Medicine, San Francisco, California, USA.
²⁷ Department of Neurology, Stanford University Medical Center, Stanford, California, USA.
²⁸ Pediatric Associates of Stockton, Stockton, California, USA.
²⁹ Division of Pediatric Neurology, Oregon Health & Science University School of Medicine, Portland, Oregon, USA.
³⁰ Stead Family Department of Pediatrics, Carver College of Medicine, University of Iowa Health Care, Iowa City, Iowa, USA.
³¹ Institute of Metabolic Disease, Baylor Scott & White Research Institute, Dallas, Texas, USA.
³² Department of Child Neurology, VU University Medical Center, Amsterdam, the Netherlands.
³³ Department of Functional Genomics, Amsterdam Neuroscience, VU University, Amsterdam, the Netherlands.
³⁴ Department of Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
³⁵ Illumina, San Diego, California, USA.

Abstract

Objective: Genome sequencing (GS) is promising for unsolved leukodystrophies, but its efficacy has not been prospectively studied.

Methods: A prospective time-delayed crossover design trial of GS to assess the efficacy of GS as a first-line diagnostic tool for genetic white matter disorders took place between December 1, 2015 and September 27, 2017. Patients were randomized to receive GS immediately with concurrent standard of care (SoC) testing, or to receive SoC testing for 4 months followed by GS.

Results: Thirty-four individuals were assessed at interim review. The genetic origin of 2 patient's leukoencephalopathy was resolved before randomization. Nine patients were stratified to the immediate intervention group and 23 patients to the delayed-GS arm. The efficacy of GS was significant relative to SoC in the immediate (5/9 [56%] vs 0/9 [0%]; Wild-Seber, p < 0.005) and delayed (control) arms (14/23 [61%] vs 5/23 [22%]; Wild-Seber, p < 0.005). The time to diagnosis was significantly shorter in the immediate-GS group (log-rank test, p = 0.04). The overall diagnostic efficacy of combined GS and SoC approaches was 26 of 34 (76.5%, 95% confidence interval = 58.8-89.3%) in <4 months, greater than historical norms of <50% over 5 years. Owing to loss of clinical equipoise, the trial design was altered to a single-arm observational study.

Interpretation: In this study, first-line GS provided earlier and greater diagnostic efficacy in white matter disorders. We provide an evidence-based diagnostic testing algorithm to enable appropriate clinical GS utilization in this population. ANN NEUROL 2020;88:264-273.

Trial registration: ClinicalTrials.gov NCT02699190.

Publication types

Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Child
Child, Preschool
Cross-Over Studies
Female
Humans
Infant
Leukoencephalopathies / diagnosis*
Leukoencephalopathies / genetics*
Male
Prospective Studies
Sequence Analysis, DNA / methods*
White Matter / pathology

Associated data

ClinicalTrials.gov/NCT02699190

Abstract

Publication types

MeSH terms

Associated data

Grants and funding