Peer-Reviewed Publication
Nat Genet2024;56(4):585-594.April 1, 2024Journal Article
Comprehensive whole-genome sequence analyses provide insights into the genomic architecture of cerebral palsy.
Darcy L Fehlings1,2, Mehdi Zarrei3,4, Worrawat Engchuan3, Neal Sondheimer2,4,5, Bhooma Thiruvahindrapuram3, Jeffrey R MacDonald3,4, Edward J Higginbotham3,6, Ritesh Thapa1, Tarannum Behlim7, Sabrina Aimola1, Lauren Switzer1, Pamela Ng7, John Wei3, Prakroothi S Danthi3, Giovanna Pellecchia3, Sylvia Lamoureux3, Karen Ho3, Sergio L Pereira3, Jill de Rijke3, Wilson W L Sung3,4, Alireza Mowjoodi3,4, Jennifer L Howe3, Thomas Nalpathamkalam3, Roozbeh Manshaei3,8, Siavash Ghaffari3,4, Joseph Whitney3, Rohan V Patel3, Omar Hamdan3, Rulan Shaath3, Brett Trost3,4, Shannon Knights2,9, Dawa Samdup10, Anna McCormick11, Carolyn Hunt9, Adam Kirton12, Anne Kawamura1,2, Ronit Mesterman13, Jan Willem Gorter13, Nomazulu Dlamini2,14,15, Daniele Merico3,16,17, Murto Hilali3, Kyle Hirschfeld3, Kritika Grover3, Nelson X Bautista3, Kara Han3, Christian R Marshall6, Ryan K C Yuen3,4,5, Padmaja Subbarao2,13,18, Meghan B Azad19, Stuart E Turvey20, Piush Mandhane21, Theo J Moraes2,22, Elinor Simons23, George Maxwell24, Michael Shevell7,25, Gregory Costain2,4,6,26, Jacques L Michaud27,28, Fadi F Hamdan28,29, Julie Gauthier28,29, Kevin Uguen28, Dimitri J Stavropoulos6,30, Richard F Wintle3, Maryam Oskoui7,25, Stephen W Scherer31,32,33
1Division of Developmental Paediatrics, Holland Bloorview Kids Rehabilitation Hospital, Toronto, Ontario, Canada.
2Department of Paediatrics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
3The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.
4Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
5Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
6Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
7Centre for Outcomes Research and Evaluation, Research Institute of the McGill University Health Centre, Montréal, Québec, Canada.
8Ted Rogers Centre for Heart Research, Cardiac Genome Clinic, The Hospital for Sick Children, Toronto, Ontario, Canada.
9Grandview Children's Centre, Oshawa, Ontario, Canada.
10Department of Pediatrics, Queen's University, Kingston, Ontario, Canada.
11Children's Hospital of Eastern Ontario and University of Ottawa, Ottawa, Ontario, Canada.
12Department of Pediatrics, Department of Clinical Neuroscience, University of Calgary, Calgary, Alberta, Canada.
13Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.
14Division of Neurology, The Hospital for Sick Children, Toronto, Ontario, Canada.
15Neurosciences and Mental Health Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.
16Deep Genomics Inc., Toronto, Ontario, Canada.
17Vevo Therapeutics Inc., San Francisco, CA, USA.
18Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
19Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada.
20Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
21Faculty of Medicine & Dentistry, Pediatrics Department, University of Alberta, Edmonton, Alberta, Canada.
22Program in Translation Medicine & Division of Respiratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
23Department of Pediatrics and Child Health, Section of Allergy and Clinical Immunology, University of Manitoba, Children's Hospital Research Institute of Manitoba, Winnipeg, Manitoba, Canada.
24Women's Health Integrated Research Center, Inova Women's Service Line, Inova Health System, Falls Church, VA, USA.
25Departments of Pediatrics and Department of Neurology and Neurosurgery, McGill University, Montréal, Québec, Canada.
26Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada.
27Departments of Pediatrics and Neurosciences, Université de Montréal, Montréal, Québec, Canada.
28CHU Sainte-Justine Azrieli Research Center, Montréal, Québec, Canada.
29Department of Pediatrics, Université de Montréal, Montréal, Québec, Canada.
30Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
31The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada. Stephen.Scherer@sickkids.ca.
32Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada. Stephen.Scherer@sickkids.ca.
33Department of Molecular Genetics and McLaughlin Centre, University of Toronto, Toronto, Ontario, Canada. Stephen.Scherer@sickkids.ca.
Abstract
We performed whole-genome sequencing (WGS) in 327 children with cerebral palsy (CP) and their biological parents. We classified 37 of 327 (11.3%) children as having pathogenic/likely pathogenic (P/LP) variants and 58 of 327 (17.7%) as having variants of uncertain significance. Multiple classes of P/LP variants included single-nucleotide variants (SNVs)/indels (6.7%), copy number variations (3.4%)…
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