PurposeCerebral palsy (CP) is the most frequent cause of motor impairment in children. While perinatal asphyxia was long considered to be the leading cause of CP, recent studies demonstrate its causation in only around 1 in 10 individuals with CP. Instead, genetic causes are increasingly demonstrated. We systematically performed clinical phenotyping and genetic investigations in a monocentric CP cohort, aiming to gain insight into the contribution of genetic variants in CP and its different subtypes. MethodsChromosomal microarray and/or trio exome sequencing were systematically performed in 337 individuals with CP between September 2017 and August 2022. Deep phenotyping was performed through clinical multidisciplinary evaluation and review of medical files. ResultsGenetic analyses resulted in an overall diagnostic yield of 38.3% (129/337). In cases with one or more comorbidities (intellectual disability, epilepsy, autism spectrum disorder), the yield increased to almost 50%. Functional enrichment analysis showed overrepresentation of the following pathways: genetic imprinting, DNA modification, liposaccharide metabolic process, neuron projection guidance and axon development. ConclusionGenetic analyses in our CP cohort, the largest monocentric study to date, demonstrated a diagnostic yield of 38.3%, highlighting the importance of genetic testing in CP. The diagnosis of a genetic disorder is essential for prognosis and clinical follow-up, as well as for family counseling. Pathway analysis points to dysregulation of general developmental and metabolic processes as well as neuronal development and function. Unravelling the role of these pathways in CP pathogenesis is instrumental for identification of CP candidate genes as well as potential therapeutic targets.