Integrating Genome and RNA Sequencing to Enhance Diagnostic Precision in Cerebral Palsy

Purpose--Cerebral palsy(CP), a non-progressive neuromuscular system disorder, shows considerable genetic diversity. This study aimed to diagnose patients with CP and explore novel diagnostic strategies.Methods--This studycohort comprised 27 children with CP and their asymptomatic parents. Genome sequencing (GS) and RNA sequencing were employed for genetic diagnostics.Results--Family-based GS identified pathogenic or likely pathogenic variants in 2 children and variants of uncertain significance variants in 7 children. Additionally,we found 216 genes with damaging de novo variant, including 3 known CP genes: PROC, WDR81, and SPTBN2. RNA-seq analysis revealed 5 candidate genes with abnormal expression and 250 candidate events with abnormal alternative splicing. Notably, highly reliable alternative splicing sites were found in DNMT1 and VPS13C. Furthermore, pathway analysis uncovered 3 abnormal pathwaysrelated to neurological functions in 2 children, with one pathway containing S1PR4 gene that harborsa deleterious de novo variant.