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

Gene-agnostic trio whole genome sequencing with AI-based variant prioritisation, followed by secondary application of a cerebral palsy gene list.

International studies indicate that 9% to 36% of people with cerebral palsy have a monogenic condition, but the utility of WGS had not been evaluated in UK NHS patients. This prospective pilot study recruited 86 individuals with cerebral palsy across five NHS trusts, using gene-agnostic trio WGS with AI-based variant prioritisation followed by secondary application of a cerebral palsy gene list; candidate variants were reviewed at multidisciplinary meetings and confirmed in an NHS Genomic Laboratory Hub before clinical reporting. Of 157 individuals approached, 86 (54.7%) consented. Pathogenic or likely pathogenic variants were identified in 11 of 86 patients (12.8%), a further 8 (9.3%) carried variants strongly suggestive of a genetic cause and 27 (31.4%) had variants of uncertain significance. In all cases with pathogenic or likely pathogenic variants, findings informed prognosis, specialist care, clinical management and familial recurrence risk; a linear discriminant analysis model on HPO terms was used to estimate the probability of a diagnostic variant.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The 12.8% figure places cerebral palsy at the lower end of already accepted indications, which is enough in practice to stop treating this clinical diagnosis as the end of the aetiological work-up. Two caveats limit transposition: a 54.7% participation rate, which exposes the study to selection bias towards atypical or familial presentations, and 31.4% variants of uncertain significance, an interpretive and emotional burden to carry in clinic. The HPO-based classification model is exploratory work on 86 patients and should not be read as a tool for selecting candidates for sequencing.

Analysis by Dr Thibaut Benquey