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Randomized Clinical Trial of First-Line Genome Sequencing in Pediatric White Matter Disorders.
Vanderver, Adeline; Bernard, Geneviève; Helman, Guy; Sherbini, Omar; Boeck, Ryan; Cohn, Jeffrey; Collins, Abigail; Demarest, Scott; Dobbins, Katherine; Emrick, Lisa; Fraser, Jamie L; Masser-Frye, Diane; Hayward, Jean; Karmarkar, Swati; Keller, Stephanie; Mirrop, Samuel; Mitchell, Wendy; Pathak, Sheel; Sherr, Elliott; van Haren, Keith; Waters, Erica; Wilson, Jenny L; Zhorne, Leah; Schiffmann, Raphael; van der Knaap, Marjo S; Pizzino, Amy; Dubbs, Holly; Shults, Justine; Simons, Cas; Taft, Ryan J.
Afiliação
  • Vanderver A; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
  • Bernard G; Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
  • Helman G; Departments of Neurology and Neurosurgery, Pediatrics, and Human Genetics, McGill University, Montreal, Quebec, Canada.
  • Sherbini O; Department of Specialized Medicine, Division of Medical Genetics, Montreal Children's Hospital and McGill University Health Centre, Montreal, Quebec, Canada.
  • Boeck R; Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.
  • Cohn J; Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
  • Collins A; Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia.
  • Demarest S; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
  • Dobbins K; Child Neurology Consultants of Austin, Austin, Texas, USA.
  • Emrick L; University of Texas at Austin Dell Medical School, Austin, Texas, USA.
  • Fraser JL; Family Medicine, Broadlands Family Practice at Ashburn, Ashburn, Virginia, USA.
  • Masser-Frye D; Department of Neurology, Anschutz Medical Campus, University of Colorado School of Medicine, Aurora, Colorado, USA.
  • Hayward J; Department of Neurology, Anschutz Medical Campus, University of Colorado School of Medicine, Aurora, Colorado, USA.
  • Karmarkar S; Walter Reed National Military Medical Center, Bethesda, Maryland, USA.
  • Keller S; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
  • Mirrop S; Division of Genetics and Metabolism, Rare Disease Institute, Children's National Hospital, Washington, District of Columbia, USA.
  • Mitchell W; George Washington University, Washington, District of Columbia, USA.
  • Pathak S; Rady Children's Hospital, San Diego, California, USA.
  • Sherr E; Department of Pediatrics, Kaiser Oakland, Oakland, California, USA.
  • van Haren K; Department of Neurology, Le Bonheur Children's Hospital, Memphis, Tennessee, USA.
  • Waters E; Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
  • Wilson JL; Division of Neurology, Department of Pediatrics, Emory University, Atlanta, Georgia, USA.
  • Zhorne L; Pediatric Associates of Austin, Austin, Texas, USA.
  • Schiffmann R; Division of Neurology, Children's Hospital of Los Angeles, Los Angeles, California, USA.
  • van der Knaap MS; Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
  • Pizzino A; Clinical Neurology, Washington University Clinical Associates, St Louis, Missouri, USA.
  • Dubbs H; Department of Neurology, Washington University School of Medicine, St Louis, Missouri, USA.
  • Shults J; Department of Neurology, University of California, San Francisco School of Medicine, San Francisco, California, USA.
  • Simons C; Department of Neurology, Stanford University Medical Center, Stanford, California, USA.
  • Taft RJ; Pediatric Associates of Stockton, Stockton, California, USA.
Ann Neurol ; 88(2): 264-273, 2020 08.
Article em En | MEDLINE | ID: mdl-32342562
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;88264-273.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Análise de Sequência de DNA / Leucoencefalopatias Idioma: En Ano de publicação: 2020 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Análise de Sequência de DNA / Leucoencefalopatias Idioma: En Ano de publicação: 2020 Tipo de documento: Article