Adeline Vanderver1,2, Geneviève Bernard3,4,5, Guy Helman6,7, Omar Sherbini1, Ryan Boeck8,9, Jeffrey Cohn10, Abigail Collins11, Scott Demarest11, Katherine Dobbins12, Lisa Emrick13, Jamie L Fraser14,15, Diane Masser-Frye16, Jean Hayward17, Swati Karmarkar18,19, Stephanie Keller20, Samuel Mirrop21, Wendy Mitchell22,23, Sheel Pathak24,25, Elliott Sherr26, Keith van Haren27, Erica Waters28, Jenny L Wilson29, Leah Zhorne30, Raphael Schiffmann31, Marjo S van der Knaap32,33, Amy Pizzino1, Holly Dubbs1, Justine Shults34, Cas Simons6,7, Ryan J Taft35. 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.
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.
Authors: Tiong Yang Tan; Oliver James Dillon; Zornitza Stark; Deborah Schofield; Khurshid Alam; Rupendra Shrestha; Belinda Chong; Dean Phelan; Gemma R Brett; Emma Creed; Anna Jarmolowicz; Patrick Yap; Maie Walsh; Lilian Downie; David J Amor; Ravi Savarirayan; George McGillivray; Alison Yeung; Heidi Peters; Susan J Robertson; Aaron J Robinson; Ivan Macciocca; Simon Sadedin; Katrina Bell; Alicia Oshlack; Peter Georgeson; Natalie Thorne; Clara Gaff; Susan M White Journal: JAMA Pediatr Date: 2017-09-01 Impact factor: 16.193
Authors: Adeline Vanderver; Cas Simons; Guy Helman; Joanna Crawford; Nicole I Wolf; Geneviève Bernard; Amy Pizzino; Johanna L Schmidt; Asako Takanohashi; David Miller; Amirah Khouzam; Vani Rajan; Erica Ramos; Shimul Chowdhury; Tina Hambuch; Kelin Ru; Gregory J Baillie; Sean M Grimmond; Ljubica Caldovic; Joseph Devaney; Miriam Bloom; Sarah H Evans; Jennifer L P Murphy; Nathan McNeill; Brent L Fogel; Raphael Schiffmann; Marjo S van der Knaap; Ryan J Taft Journal: Ann Neurol Date: 2016-05-09 Impact factor: 10.422
Authors: Y Akwa; D E Hassett; M L Eloranta; K Sandberg; E Masliah; H Powell; J L Whitton; F E Bloom; I L Campbell Journal: J Immunol Date: 1998-11-01 Impact factor: 5.422
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Authors: Gaby Schobers; Jolanda H Schieving; Michèl A A P Willemsen; Lisenka E L M Vissers; Helger G Yntema; Maartje Pennings; Rolph Pfundt; Ronny Derks; Tom Hofste; Ilse de Wijs; Nienke Wieskamp; Simone van den Heuvel; Jordi Corominas Galbany; Christian Gilissen; Marcel Nelen; Han G Brunner; Tjitske Kleefstra; Erik-Jan Kamsteeg Journal: Genome Med Date: 2022-06-17 Impact factor: 15.266
Authors: Agatha Schlüter; Agustí Rodríguez-Palmero; Edgard Verdura; Valentina Vélez-Santamaría; Montserrat Ruiz; Stéphane Fourcade; Laura Planas-Serra; Juan José Martínez; Cristina Guilera; Marisa Girós; Rafael Artuch; María Eugenia Yoldi; Mar O'Callaghan; Angels García-Cazorla; Judith Armstrong; Itxaso Marti; Elisabet Mondragón Rezola; Claire Redin; Jean Louis Mandel; David Conejo; Concepción Sierra-Córcoles; Sergi Beltrán; Marta Gut; Elida Vázquez; Mireia Del Toro; Mónica Troncoso; Luis A Pérez-Jurado; Luis G Gutiérrez-Solana; Adolfo López de Munain; Carlos Casasnovas; Sergio Aguilera-Albesa; Alfons Macaya; Aurora Pujol Journal: Neurology Date: 2022-01-10 Impact factor: 9.910