Systematic reanalysis of genomic data from the Australian Cerebral Palsy Biobank cohort

Abstract

Background: Cerebral palsy (CP) is a clinical descriptor, not a distinct disorder. It encompass a spectrum of non-degenerative movement disorders, frequently accompanied by additional neurodevelopmental features e.g. intellectual disability (~50%), epilepsy (~30%), speech impairments (~60%), vision impairments (~40%) and autism spectrum disorders (~9%). The contribution of genetics to CP etiology is being increasingly recognised. The Australian Cerebral Palsy Biobank (ACPB) is an internationally unique resource, containing DNA, patient cell lines and clinical data for >500 Australians with CP, mostly recruited from CP Registers in Australia between 2010-2018 and clinically unselected. Methods: Exome, genome or gene panel was performed between 2012-2023, with ~350 cases also undergoing RNA sequencing and ~200 profiled for genome-wide epigenetic signatures. We performed systematic reanalysis of our combined genomic data with updated bioinformatic pipelines, and incorporationg our curated CP gene-list (of n>500 CP implicated genes) with updated annotations and gene-disease associations. Results: With the addition of omics technologies, at least ¼ of the ACPB cohort have a genetic cause for their CP, including known and novel genetic disorders. Our investigations and review of the literature identified variants in SPAST, ATL1, CACNA1A, CTNNB1, KCNQ2, ATM, PAFAH1B1/LIS1, COL4A1 and SPR as the most frequent genetic causes of CP. Conclusions: These results highlight the genetic overlap between CP and other neurodevelopmental and movement disorders. Importantly, genetic findings are not limited to children without other CP-associated risk factors, suggesting that broad genomic testing is warranted in this frequently overlooked group of rare disorders.