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

• Published in: Nature genetics Vol. 56; no. 4; pp. 585 - 594
• Main Authors: Fehlings, Darcy L., Zarrei, Mehdi, Engchuan, Worrawat, Sondheimer, Neal, Thiruvahindrapuram, Bhooma, MacDonald, Jeffrey R., Higginbotham, Edward J., Thapa, Ritesh, Behlim, Tarannum, Aimola, Sabrina, Switzer, Lauren, Ng, Pamela, Wei, John, Danthi, Prakroothi S., Pellecchia, Giovanna, Lamoureux, Sylvia, Ho, Karen, Pereira, Sergio L., de Rijke, Jill, Sung, Wilson W. L., Mowjoodi, Alireza, Howe, Jennifer L., Nalpathamkalam, Thomas, Manshaei, Roozbeh, Ghaffari, Siavash, Whitney, Joseph, Patel, Rohan V., Hamdan, Omar, Shaath, Rulan, Trost, Brett, Knights, Shannon, Samdup, Dawa, McCormick, Anna, Hunt, Carolyn, Kirton, Adam, Kawamura, Anne, Mesterman, Ronit, Gorter, Jan Willem, Dlamini, Nomazulu, Merico, Daniele, Hilali, Murto, Hirschfeld, Kyle, Grover, Kritika, Bautista, Nelson X., Han, Kara, Marshall, Christian R., Yuen, Ryan K. C., Subbarao, Padmaja, Azad, Meghan B., Turvey, Stuart E., Mandhane, Piush, Moraes, Theo J., Simons, Elinor, Maxwell, George, Shevell, Michael, Costain, Gregory, Michaud, Jacques L., Hamdan, Fadi F., Gauthier, Julie, Uguen, Kevin, Stavropoulos, Dimitri J., Wintle, Richard F., Oskoui, Maryam, Scherer, Stephen W.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.04.2024; Nature Publishing Group
• Subjects: 692/308/2056; 692/699/375/346; Agriculture; Animal Genetics and Genomics; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cerebral palsy; Cerebral Palsy - genetics; Child; Children; Children & youth; Copy number; Developmental disabilities; DNA Copy Number Variations - genetics; Families & family life; Gene Function; Gene sequencing; Genes; Genetic analysis; Genomes; Genomics; Human Genetics; Humans; Mutation; Mutation rates; Nervous system; Nucleotide sequence; Nucleotides; Pediatrics; Phenotypes; Risk assessment; Whole Genome Sequencing
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/s41588-024-01686-x

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. Whole-genome sequencing in a Canadian cohort of 327 children with cerebral palsy compared to pediatric controls identifies novel pathogenic single-nucleotide variants/indels and copy number variations. In addition, mitochondrial variants in known disease genes were identified. This highlights the importance of genomic testing for individuals with cerebral palsy.