Improving Cerebral Palsy Genetics Research through Family Involvement, Epidemiology, and a Sibling Design Approach

Abstract

BACKGROUND: This thesis addresses key challenges in CP genomics research: understanding community perspectives, developing a CP gene list and common data elements (CDEs), and exploring whether siblings of children with CP have increased NDD risk and share rare genetic variants.

METHODS: A survey co-developed with people with lived experience examined community perspectives on genetics. A systematic review (2010–2024; studies >10 children with CP) identified recurrent pathogenic/likely pathogenic (P/LP) variants. A Delphi consensus process established CDEs for CP genetic research. A population-based linked dataset (NSW births 2001–2010; followed to 2017) examined NDD outcomes in siblings of children with CP. A pilot exome sequencing study explored rare clinically relevant variants in children with CP and their siblings with NDDs.

RESULTS: Trust and communication were identified as key to community participation in genetic research. The systematic review identified 379 genes with P/LP variants; 85 in ≥3 individuals, 6 from high-confidence studies. Inconsistent phenotype reporting limited genotype-phenotype analyses. 107 CDEs were established (10 mandatory, 42 core, 41 recommended, 17 exploratory). Ten percent of families with a child with CP had another child with an NDD. Siblings of children with CP had a two-fold increased NDD risk versus unaffected siblings, but risk was comparable to siblings of children with other NDDs. P/LP variants were identified in two children; sibships shared rare predicted-deleterious variants, but none were clinically relevant.

CONCLUSIONS: People with CP support genetic research, though more diverse representation is needed. A curated gene list supports genotype-phenotype and CDEs harmonise interpretation and data collection. CP siblings have increased NDD risk, highlighting the need for surveillance and early intervention. Further research is warranted to understand causal pathways underlying multiple disabilities within families.