Unmasking genetic etiologies in neurodevelopmental disorders characterized by Cerebral Palsy: insights from...

Cerebral Palsy (CP) is characterized by permanent, non-degenerative motor function deficits with increasing evidence of genetic contributions. Although prenatal and perinatal risk factors are well recognized, the underlying etiopathology remains incompletely understood. This study aimed to improve diagnostic accuracy and elucidate the genetic architecture of CP and CP-like phenotypes through systematic genomic analyses.

Patients with clinically confirmed CP or CP-like presentations were recruited, and biological samples were stored in the ACU-Biobank. Whole-exome and whole-genome sequencing data were analyzed using a validated in-house pipeline incorporating comprehensive variant filtering, prioritization, and re-phenotyping.

Pathogenic or likely pathogenic variants were identified in 36.4% (24/66) of patients, while variants of uncertain significance (VUS) were detected in 25.8% (17/66). Identified variants involved genes such as SPAST, KIF1A, PLA2G6, CTNNB1, L1CAM, and SYNGAP1. These results demonstrate a substantial contribution of rare monogenic variants to CP and CP-like phenotypes, reflecting extensive genetic heterogeneity.

Our findings support the increasing evidence that genetic factors contribute significantly to CP etiology and emphasize the importance of integrating genomic testing into clinical evaluation. The systematic use of exome and genome sequencing improves diagnostic yield and enables genotype-informed classification, aiding targeted management and genetic counseling for affected individuals.