Comprehensive whole-genome sequence analyses provide insights into the genomic architecture of cerebral palsy.

Journal: Nature genetics

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Affiliated Institutions:  Division of Developmental Paediatrics, Holland Bloorview Kids Rehabilitation Hospital, Toronto, Ontario, Canada. The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada. Department of Paediatrics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. Centre for Outcomes Research and Evaluation, Research Institute of the McGill University Health Centre, Montréal, Québec, Canada. Department of Pediatrics, Queen's University, Kingston, Ontario, Canada. Children's Hospital of Eastern Ontario and University of Ottawa, Ottawa, Ontario, Canada. Grandview Children's Centre, Oshawa, Ontario, Canada. Department of Pediatrics, Department of Clinical Neuroscience, University of Calgary, Calgary, Alberta, Canada. Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada. Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada. Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada. Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada. Faculty of Medicine & Dentistry, Pediatrics Department, University of Alberta, Edmonton, Alberta, Canada. Department of Pediatrics and Child Health, Section of Allergy and Clinical Immunology, University of Manitoba, Children's Hospital Research Institute of Manitoba, Winnipeg, Manitoba, Canada. Women's Health Integrated Research Center, Inova Women's Service Line, Inova Health System, Falls Church, VA, USA. Departments of Pediatrics and Neurosciences, Université de Montréal, Montréal, Québec, Canada. CHU Sainte-Justine Azrieli Research Center, Montréal, Québec, Canada. The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada. Stephen.Scherer@sickkids.ca.

Abstract summary 

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%) and mitochondrial mutations (1.5%). The COL4A1 gene had the most P/LP SNVs. We also analyzed two pediatric control cohorts (n = 203 trios and n = 89 sib-pair families) to provide a baseline for de novo mutation rates and genetic burden analyses, the latter of which demonstrated associations between de novo deleterious variants and genes related to the nervous system. An enrichment analysis revealed previously undescribed plausible candidate CP genes (SMOC1, KDM5B, BCL11A and CYP51A1). A multifactorial CP risk profile and substantial presence of P/LP variants combine to support WGS in the diagnostic work-up across all CP and related phenotypes.

Authors & Co-authors:  Fehlings Zarrei Engchuan Sondheimer Thiruvahindrapuram MacDonald Higginbotham Thapa Behlim Aimola Switzer Ng Wei Danthi Pellecchia Lamoureux Ho Pereira de Rijke Sung Mowjoodi Howe Nalpathamkalam Manshaei Ghaffari Whitney Patel Hamdan Shaath Trost Knights Samdup McCormick Hunt Kirton Kawamura Mesterman Gorter Dlamini Merico Hilali Hirschfeld Grover Bautista Han Marshall Yuen Subbarao Azad Turvey Mandhane Moraes Simons Maxwell Shevell Costain Michaud Hamdan Gauthier Uguen Stavropoulos Wintle Oskoui Scherer

Study Outcome 

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Statistics
Citations :  McIntyre, S. et al. Global prevalence of cerebral palsy: a systematic analysis. Dev. Med. Child Neurol. 64, 1494–1506 (2022).
Authors :  64
Identifiers
Doi : 10.1038/s41588-024-01686-x
SSN : 1546-1718
Study Population
Male,Female
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Publication Country
United States