Whole genome sequencing in cerebral palsy: a UK paediatric pilot study

Background Prior international studies indicate that 9–36% of people with cerebral palsy (CP) have a monogenic condition. However, the utility of whole genome sequencing (WGS) as a diagnostic tool for United Kingdom (UK) National Health Service (NHS) patients has not been evaluated. Methods This prospective pilot study recruited 86 individuals with CP from specialist clinics in Bedford, Cambridge, Colchester, Newcastle, and Luton NHS Foundation Trusts. Gene-agnostic trio WGS was performed using AI-based variant prioritisation, with subsequent application of a CP gene list. Candidate diagnostic pathogenic (P) or likely pathogenic (LP) variants were reviewed at multidisciplinary meetings and confirmed in an NHS Genomic Laboratory Hub prior to issuing a clinical report. The use of human phenotype ontology (HPO) terms was evaluated to estimate probability of a diagnostic variant using a supervised linear discriminant analysis (PCA + LDA) model. Findings 86/157 (54.7%) individuals approached consented to the study. Variants meeting P/LP diagnostic criteria were identified in 11/86 cases (12.8%). 8/86 participants (9.3%) carried variants strongly suggestive of disease causation. Variants of uncertain significance were identified in 27/86 cases (31.4%). In all cases with P/LP variants, findings informed patient prognosis, specialist care, clinical management, and familial recurrence risk. Machine learning approaches were used to segregate the probability of diagnosis for participants based on HPO terms. Interpretation WGS is clinically useful for diagnosis and management of genetic conditions associated with CP in the UK. Validation of these findings in a larger cohort is warranted. Funding Rosetrees Charitable Trust, Isaac Newton Trust, NIHR Cambridge Biomedical Research Centre, and the Wellcome Trust.