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Abstract Details

Whole Genome Sequencing to Resolve the Genomic Architecture of Cerebral Palsy in a Canadian Cohort
Child Neurology and Developmental Neurology
P13 - Poster Session 13 (8:00 AM-9:00 AM)
4-003
To capture the full extent of genomic contributions to cerebral palsy (CP) in an unselected cohort.

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.
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.
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.
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.   
Authors/Disclosures
Maryam Oskoui, MD, FÂ鶹´«Ã½Ó³»­ (Montreal Children's Hospital - McGill University Health Centre)
PRESENTER 		The institution of Dr. Oskoui has received research support from Hoffmann-La Roche Ltd. The institution of Dr. Oskoui has received research support from Muscular Dystrophy Canada. The institution of Dr. Oskoui has received research support from Canadian Institutes of Health Research. The institution of Dr. Oskoui has received research support from Santhera. The institution of Dr. Oskoui has received research support from Novartis. The institution of Dr. Oskoui has received research support from Fonds de Recherche du Québec. The institution of Dr. Oskoui has received research support from Biogen.
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Karen Ho, MD No disclosure on file
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Adam Kirton, MD (Alberta Children'S Hospital) Dr. Kirton has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Multiple. The institution of Dr. Kirton has received research support from Multiple.
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Michael I. Shevell, MD, FÂ鶹´«Ã½Ó³»­ (Montreal Children's Hospital-McGill University Health Centre) Dr. Shevell has nothing to disclose.
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