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

Darcy L Fehlings^#^{1

2}, Mehdi Zarrei^#^{3

4}, Worrawat Engchuan³, Neal Sondheimer^{2

4

5}, Bhooma Thiruvahindrapuram³, Jeffrey R MacDonald^{3

4}, Edward J Higginbotham^{3

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 Sung^{3

4}, Alireza Mowjoodi^{3

4}, Jennifer L Howe³, Thomas Nalpathamkalam³, Roozbeh Manshaei^{3

8}, Siavash Ghaffari^{3

4}, Joseph Whitney³, Rohan V Patel³, Omar Hamdan³, Rulan Shaath³, Brett Trost^{3

4}, Shannon Knights^{2

9}, Dawa Samdup¹⁰, Anna McCormick¹¹, Carolyn Hunt⁹, Adam Kirton¹², Anne Kawamura^{1

2}, Ronit Mesterman¹³, Jan Willem Gorter¹³, Nomazulu Dlamini^{2

14

15}, Daniele Merico^{3

16

17}, Murto Hilali³, Kyle Hirschfeld³, Kritika Grover³, Nelson X Bautista³, Kara Han³, Christian R Marshall⁶, Ryan K C Yuen^{3

4

5}, Padmaja Subbarao^{2

13

18}, Meghan B Azad¹⁹, Stuart E Turvey²⁰, Piush Mandhane²¹, Theo J Moraes^{2

22}, Elinor Simons²³, George Maxwell²⁴, Michael Shevell^{7

25}, Gregory Costain^{2

4

6

26}, Jacques L Michaud^{27

28}, Fadi F Hamdan^{28

29}, Julie Gauthier^{28

29}, Kevin Uguen²⁸, Dimitri J Stavropoulos^{6

30}, Richard F Wintle³, Maryam Oskoui^{7

25}, Stephen W Scherer^{31

32

33}

Affiliations

¹ Division of Developmental Paediatrics, Holland Bloorview Kids Rehabilitation Hospital, Toronto, Ontario, Canada.
² Department of Paediatrics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
³ The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁴ Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁵ Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
⁶ Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁷ Centre for Outcomes Research and Evaluation, Research Institute of the McGill University Health Centre, Montréal, Québec, Canada.
⁸ Ted Rogers Centre for Heart Research, Cardiac Genome Clinic, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁹ Grandview Children's Centre, Oshawa, Ontario, Canada.
¹⁰ Department of Pediatrics, Queen's University, Kingston, Ontario, Canada.
¹¹ Children's Hospital of Eastern Ontario and University of Ottawa, Ottawa, Ontario, Canada.
¹² Department of Pediatrics, Department of Clinical Neuroscience, University of Calgary, Calgary, Alberta, Canada.
¹³ Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.
¹⁴ Division of Neurology, The Hospital for Sick Children, Toronto, Ontario, Canada.
¹⁵ Neurosciences and Mental Health Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.
¹⁶ Deep Genomics Inc., Toronto, Ontario, Canada.
¹⁷ Vevo Therapeutics Inc., San Francisco, CA, USA.
¹⁸ Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
¹⁹ Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada.
²⁰ Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
²¹ Faculty of Medicine & Dentistry, Pediatrics Department, University of Alberta, Edmonton, Alberta, Canada.
²² Program in Translation Medicine & Division of Respiratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
²³ 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.
²⁴ Women's Health Integrated Research Center, Inova Women's Service Line, Inova Health System, Falls Church, VA, USA.
²⁵ Departments of Pediatrics and Department of Neurology and Neurosurgery, McGill University, Montréal, Québec, Canada.
²⁶ Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada.
²⁷ Departments of Pediatrics and Neurosciences, Université de Montréal, Montréal, Québec, Canada.
²⁸ CHU Sainte-Justine Azrieli Research Center, Montréal, Québec, Canada.
²⁹ Department of Pediatrics, Université de Montréal, Montréal, Québec, Canada.
³⁰ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
³¹ The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada. Stephen.Scherer@sickkids.ca.
³² Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada. Stephen.Scherer@sickkids.ca.
³³ Department of Molecular Genetics and McLaughlin Centre, University of Toronto, Toronto, Ontario, Canada. Stephen.Scherer@sickkids.ca.

^# Contributed equally.

PMID: 38553553
DOI: 10.1038/s41588-024-01686-x

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

Darcy L Fehlings et al. Nat Genet. 2024 Apr.

. 2024 Apr;56(4):585-594.

doi: 10.1038/s41588-024-01686-x. Epub 2024 Mar 29.

Authors

Affiliations

¹ Division of Developmental Paediatrics, Holland Bloorview Kids Rehabilitation Hospital, Toronto, Ontario, Canada.
² Department of Paediatrics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
³ The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁴ Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁵ Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
⁶ Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁷ Centre for Outcomes Research and Evaluation, Research Institute of the McGill University Health Centre, Montréal, Québec, Canada.
⁸ Ted Rogers Centre for Heart Research, Cardiac Genome Clinic, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁹ Grandview Children's Centre, Oshawa, Ontario, Canada.
¹⁰ Department of Pediatrics, Queen's University, Kingston, Ontario, Canada.
¹¹ Children's Hospital of Eastern Ontario and University of Ottawa, Ottawa, Ontario, Canada.
¹² Department of Pediatrics, Department of Clinical Neuroscience, University of Calgary, Calgary, Alberta, Canada.
¹³ Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.
¹⁴ Division of Neurology, The Hospital for Sick Children, Toronto, Ontario, Canada.
¹⁵ Neurosciences and Mental Health Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.
¹⁶ Deep Genomics Inc., Toronto, Ontario, Canada.
¹⁷ Vevo Therapeutics Inc., San Francisco, CA, USA.
¹⁸ Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
¹⁹ Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada.
²⁰ Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
²¹ Faculty of Medicine & Dentistry, Pediatrics Department, University of Alberta, Edmonton, Alberta, Canada.
²² Program in Translation Medicine & Division of Respiratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
²³ 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.
²⁴ Women's Health Integrated Research Center, Inova Women's Service Line, Inova Health System, Falls Church, VA, USA.
²⁵ Departments of Pediatrics and Department of Neurology and Neurosurgery, McGill University, Montréal, Québec, Canada.
²⁶ Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada.
²⁷ Departments of Pediatrics and Neurosciences, Université de Montréal, Montréal, Québec, Canada.
²⁸ CHU Sainte-Justine Azrieli Research Center, Montréal, Québec, Canada.
²⁹ Department of Pediatrics, Université de Montréal, Montréal, Québec, Canada.
³⁰ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
³¹ The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada. Stephen.Scherer@sickkids.ca.
³² Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada. Stephen.Scherer@sickkids.ca.
³³ Department of Molecular Genetics and McLaughlin Centre, University of Toronto, Toronto, Ontario, Canada. Stephen.Scherer@sickkids.ca.

^# Contributed equally.

PMID: 38553553
DOI: 10.1038/s41588-024-01686-x

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%) 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.

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References

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

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

Authors

Affiliations

Abstract

References

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Research Materials

Miscellaneous