A Phenotypic Paradigm for Cerebral Palsy Genetics.

Area of Science:

• Genetics
• Neurology
• Pediatrics

Background:

• Genetic variants are implicated in a subset of cerebral palsy (CP) cases.
• Over 515 genes have been linked to CP, but causal evidence varies significantly.

Purpose of the Study:

• To develop a statistical approach to assess the association between genetic disorders and CP risk.
• To identify genes with robust evidence for causality in CP.
• To apply these findings to a pediatric CP cohort for precision medicine insights.

Main Methods:

• Developed a statistical method treating CP as a phenotype influenced by genetic disorders.
• Conducted comprehensive literature curation to evaluate CP gene associations.
• Analyzed a cohort of 460 children with CP using next-generation sequencing.

Main Results:

• Literature analysis confirmed significant CP association for only 89 out of 515 genes.
• Identified pathogenic or likely pathogenic variants in 60 genes in 15.8% of the CP cohort.
• Only 16 of these 60 genes had strong prior evidence for CP association from literature.

Conclusions:

• A refined, stratified approach to attributing genetic causality in CP is necessary.
• This method can enhance the identification of genetic drivers of CP.
• Findings support the advancement of precision genomic medicine for children with cerebral palsy.