Whole Genome Sequencing to Resolve the Genomic Architecture of Cerebral Palsy in a Canadian Cohort
Maryam Oskoui1, Mehdi Zarrei2, Worrawat Engchuan3, Neal Sondheimer4, Bhooma Thiruv3, Edward Higginbotham2, Ritesh Thapa5, Tarannum Behlim7, Sabrina Aimola5, John Wei2, Prakroothi Danthi2, Giovanna Pellecchia2, Karen Ho2, Jill de Rijke2, Jennifer Howe2, Thomas Nalpathamkalam2, Roozbeh Manshaei2, Joseph Whitney2, Rohan Patel2, Omar Hamdan2, Rulan Shaath6, Shannon Knights8, Brett Trost3, Dawa Samdup9, ANNA MCCORMICK10, Carolyn Hunt8, Adam Kirton11, Anne Kawamura5, Ronit Mesterman12, Jan Willem Gorter13, Nomazulu Dlamini3, Daniele Merico14, Ryan Yuen2, Michael Shevell15, Dimitri Stavropoulos3, Richard Wintle2, Darcy Fehlings6, Stephen Scherer16
1Pediatric Neurology, McGill University, 2Centre for Applied Genomics, 3The Hospital for Sick Children, 4University of Toronto, 5Holland Bloorview Kids Rehabilitation Hospital, 6Developmental Paediatrics, Holland Bloorview Kids Rehabilitation Hospital, 7Research Institute of the McGill University Health Centre, 8Grandview Children's Centre, 9Queen's University, 10Children's Hospital of Eastern Ontario, 11Alberta Children'S Hospital, 12University of Calgary, 13McMaster University, 14Deep Genomics, 15Montreal Children's Hospital-McGill University Health Centre, 16SickKids
Objective:
To capture the full extent of genomic contributions to cerebral palsy (CP) in an unselected cohort.
Background:
CP is the most common childhood physical disability. It is increasingly recognized that genomic changes can contribute to at least some of the clinical features and phenotypes of individuals with CP . The uncovering of rare variants can result in a degree of diagnostic confusion, with some known disorders labeled as CP “mimics”. This has led to debate about the validity of a clinical diagnosis of CP in individuals with a “genetic diagnosis”. Resolution of these discussions will be made easier by the comprehensive understanding of the full range of genomic factors contributing to CP features and phenotypes in a large, prospectively collected cohort, with analysis of parental samples to assist in identification of inherited and de novo variation, and paired with thorough clinical phenotype assessments.
Design/Methods:
We report on whole genome sequencing in 327 unselected children with cerebral palsy (CP) and their biologic parents recruited from CP-NET and the Canadian CP Registry.
Results:
We identified clinically relevant variants in 29.1 % (95/327) with 11.3% classified as pathogenic/likely pathogenic (P/LP) and 17.8% as variants of unknown significance. Multiple classes of rare variants included copy number variations (16.5%), damaging single nucleotide variants (SNV) and indels (12.5%), mitochondrial variants (1.5%) and structural variants (0.6%). COL4A1, a gene that encodes the alpha-1 subunit of collagen type IV, was the most frequent SNV (4 cases). Mitochondrial variants were associated with mitochondrial phenotypes including mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). A burden analysis demonstrated associations between de novo damaging variants and genes related to neuro-functions, nervous system and FMR1 target genes.
Conclusions:
A multifactorial CP risk profile and high rate of P/LP variants (11.3%) combine to support genomic testing, including mitochondrial variants, in the diagnostic work-up across all CP phenotypes.