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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Data availability
WGS data from CP families from the Canadian CP Registry and control data from the CHILD cohort are available at the European Genome–Phenome Archive (EGA; Canadian CP Registry: https://ega-archive.org/dacs/EGAC00001003068; CHILD: https://ega-archive.org/dacs/EGAC00001002953). WGS data from CP-NET are stored in the Brain-CODE Neuroinformatics Platform (https://doi.org/10.60955/fszr-5q79)97. Access to the EGA datasets is governed by a Data Access Committee with primary contact via author S.W.S. Access to the Brain-CODE dataset is governed by a Data Access Committee managed by the Ontario Brain Institute, with primary contacts via authors R.F.W. and D.L.F. Control data from subjects enrolled in the Inova cohort were not consented for deposition in public databases and are thus available on request from author G.M. Source data are provided with this paper.
Code availability
The present study did not use any customized code or software.
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Acknowledgements
This research was conducted in part through the Childhood Cerebral Palsy Neuroscience Discovery Network (CP-NET) with the support of the Ontario Brain Institute, an independent nonprofit corporation, funded by the Ontario Government. The present study was also funded by Project Grants from the Canadian Institutes of Health Research (grant nos. PJT-153004 and PJT-175329 to R.K.C.Y.), the Research Foundation of the Cerebral Palsy Alliance (grant no. PG4516), Debbie and Don Morrison for support of the CHILD study and the University of Toronto McLaughlin Centre. The Canadian CP Registry was funded by Kids Brain Health Network. R.K.C.Y. is supported by the Hospital for Sick Children’s Research Institute, SickKids Catalyst Scholar in Genetics, Brain Canada and the Azrieli Foundation. CHILD was initially funded by CIHR and AllerGen NCE, and receives support from Women and Children’s Health Research Institute at the University of Alberta (to P.M.). Work at The Centre for Applied Genomics (TCAG) at the Hospital for Sick Children is funded by the Canada Foundation for Innovation (CGEn-MSI, Innovation Fund) and Genome Canada through Ontario Genomics. We thank M. Lorenti for technical assistance with sample preparation and V. Jha, J. Sangster and S. McPherson for assistance with variant validation. We acknowledge Illumina, Inc. for providing sequencing reagents for the CHILD and Inova control cohorts. M.B.A., P.S. and S.E.T. hold Canada Research Chairs. M.O. is a Research Scholar of the Fonds de Recherche du Québec-Santé. During the work presented in this article, J.W.G. held the Scotiabank Chair in Child Health Research at McMaster University. S.W.S. holds the Northbridge Chair in Paediatric Research, a joint hospital–university chair across the University of Toronto, the Hospital for Sick Children and the SickKids Foundation. We thank all participant families for their dedication and commitment to advancing health research.
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D.L.F., R.F.W., M.O., M.Z., W.E., S.W.S., A. McCormick, A. Kirton, C.H., D.S., J.W.G., N.D., R. Mesterman, S.K., M.S. and A. Kawamura conceived the project. D.L.F., M.O., A. McCormick, A. Kirton, C.H., D.S., J.W.G., N.D. R. Mesterman, S.K., M.S., A. Kawamura and R.F.W. collected the data. M.Z., B. Trost, W.E., J.R.M., E.J.H., B. Thiruvahindrapuram, M.B.A., G.P., J. Wei, R.F.W., R.K.C.Y., S.W.S., D.L.F., M.O., N.S., P.S., S.E.T., P.M., T.J.M., E.S., G.M., D.M., D.J.S., R. Manshaei, T.N., R.S., S.G., K. Ho, J.d.R., W.W.L.S., A. Mowjoodi, G.C., J.L.M., C.R.M., F.F.H., J.G. and K.U. provided the methodology and interpreted the data. S.L., J.d.R., M.H., K. Han, K.G., N.X.B. and K. Hirschfeld validated the data. S.W.S., D.L.F. and M.O. provided the resources. B. Thiruvahindrapuram, J.R.M., J.W., P.M., P.S.D., R.V.P., O.H. and W.W.L.S. curated the data. W.E. and G.P. visualized the data. S.W.S., D.L.F., M.O. and R.F.W. supervised the project. R.F.W., S.L.P., S.A., R.T., P.N., T.B., L.S. and J.L.H. were project administrators. S.W.S., D.L.F., R.F.W., A. McCormick, A. Kirton, C.H., D.S., J.W.G., N.D., R. Mesterman, S.K., M.O., M.S. and A. Kawamura acquired the funding.
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Illumina, Inc. provided sequencing reagents for the CHILD and Inova control cohorts. S.W.S. is on the Scientific Advisory Committee of Population Bio, Inc. and serves as a Highly Cited Academic Advisor for the King Abdulaziz University. R.F.W. discloses consulting activities for Guidepoint Global, GLG and Bioinformatics LLC, not related to the present study. D.M. was employed by Deep Genomics at the time of the study and some annotation tools were provided by Deep Genomics. D.J.S. has equity in PhenoTips. The other authors declare no competing interests.
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Fehlings, D.L., Zarrei, M., Engchuan, W. et al. Comprehensive whole-genome sequence analyses provide insights into the genomic architecture of cerebral palsy. Nat Genet 56, 585–594 (2024). https://doi.org/10.1038/s41588-024-01686-x
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DOI: https://doi.org/10.1038/s41588-024-01686-x
