The Genetic Puzzle of Cerebral Palsy: Results of a Monocentric Study.

Background: Cerebral palsy (CP) is the most frequent cause of motor impairment in children. Although perinatal asphyxia was long considered to be the leading cause of CP, recent studies demonstrate its causation in only around one 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.

Methods: Chromosomal 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.

Results: Genetic analyses resulted in an overall diagnostic yield of 38.3% (129 of 337). In cases with one or more comorbidities (intellectual disability, epilepsy, autism spectrum disorder), the yield increased to almost 50%. Functional enrichment analysis showed over-representation of the following pathways: genetic imprinting, DNA modification, liposaccharide metabolic process, neuron projection guidance, and axon development.

Conclusions: Genetic 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. Unraveling the role of these pathways in CP pathogenesis is instrumental for the identification of CP candidate genes as well as potential therapeutic targets.