Cerebral Palsy

van Eyk, C. L., Fahey, M. C., & Gecz, J. (2023). Redefining cerebral palsies as a diverse group of neurodevelopmental disorders with genetic aetiology. Nature Reviews Neurology, 19(9), 542-555. 10.1038/s41582-023-00847-6

This review provides a comprehensive view of current knowledge of the genomic causes of cerebral palsy and the state of the field, with a specific focus on improving knowledge about the role of genetics amongst neurologists who are frequently on the front-line diagnosing and caring for children with cerebral palsy and their families. Our thorough review of the literature identified >500 genes with reported association with CP in the literature, 190 of which were recurrently reported. We also demonstrate for the first time a high level of genetic overlap with the developmental and epileptic encephalopathies which has been previously unappreciated.

Kayumi, S., Pérez-Jurado, L. A., Palomares, M., Rangu, S., Sheppard, S. E., Chung, W. K., . . . Corbett, M. A. (2022). Genomic and phenotypic characterization of 404 individuals with neurodevelopmental disorders caused by CTNNB1 variants. Genetics in Medicine, 24(11), 2351-2366. 10.1016/j.gim.2022.08.006

This paper systematically assesses  the clinical presentation of a large cohort with genetic variants in a gene called CTNNB1 which is the most common monogenic (single mutation) cause of cerebral palsy. In previous studies, a genetic diagnosis of CTNNB1-syndrome was considered as grounds to remove a CP diagnosis, however this study demonstrated that a clinical diagnosis of CP is appropriate and should be given to individuals with CTNNB1 variants associated with nonprogressive lower extremity hypertonia. This finding highlights the importance of early and equitable access to genomic testing regardless of clinical labels.

Jin, S. C., Lewis, S. A., Bakhtiari, S., Zeng, X., Sierant, M. C., Shetty, S., . . . Kruer, M. C. (2020). Mutations disrupting neuritogenesis genes confer risk for cerebral palsy. Nature Genetics, 52(10), 1046-1056. 10.1038/s41588-020-0695-1

This publication reports a large, international collaborative study of 250 trios (parents plus child with CP) which builds on our seminal genetic investigations (McMichael et al. 2015). It was the first study to demonstrate statistical enrichment of damaging de novo (new) genetic variants in children with CP when compared to controls. Data from this study is continuing to result in identification of genetic diagnoses, including several novel genetic disorders.

MacLennan, A. H., Lewis, S., Moreno-De-Luca, A., Fahey, M., Leventer, R. J., McIntyre, S., . . . Gecz, J. (2019). Genetic or Other Causation Should Not Change the Clinical Diagnosis of Cerebral Palsy. Journal of Child Neurology, 34(8), 472-476. https://doi.org/10.1177/0883073819840449

This Clinical Consensus Statement of the International Cerebral Palsy Genomics Consortium (ICPGC) stems from discussions at the 2nd Annual ICPGC meeting in 2018 and is based on robust discussion about whether a clinical diagnosis of cerebral palsy should be revised given genetic findings. This publication reports the consensus of the ICPGC: that the clinical diagnosis of cerebral palsy should not change despite the identification of a genetic or non-genetic cause if the person exhibits a non-progressive permanent disorder of movement and posture. This is a crucial clinical guideline to align CP with other neurodevelopmental disorders (e.g. epilepsy, autism, intellectual disability), and ensures accurate surveillance of CP rates and access to appropriate clinical care for children with CP.

McMichael, G., Bainbridge, M., Haan, E., Corbett, M., Gardner, A., Thompson, S., . . . MacLennan, A. (2015). Whole-exome sequencing points to considerable genetic heterogeneity of cerebral palsy. Molecular Psychiatry, 20(2), 176-182. 10.1038/mp.2014.189

This seminal study pioneered genomic investigations in cerebral palsy. It describes findings from the first systematic investigation genomic investigation of children with CP, showing that 14% had genetic variants that were considered to be causative. Prior to this study, estimates of genetic contribution to CP were around 1-2% of cases, with the long-held belief that CP was always the result of “birth injury” or perinatal asphyxia leading to health inequality in this patient group.

Funded by Medical Research Future Fund Genomic Health Futures Mission Grant to Prof Jozef Gecz and Dr Clare van Eyk

Cerebral palsy (CP) is the most common motor disability in children, with prevalence of 1/700 in Australia and major economic and quality of life impacts. It is a heterogeneous disorder, diagnosed based on clinical criteria, not pathology or aetiology. Despite this, current care pathways are homogeneous. Perinatal asphyxia, once believed to be a leading cause of CP, has been shown to be responsible for <10% of cases. In contrast, monogenic causes are responsible for >25%, with >50% of these children likely to benefit from personalised medicine. In this project, we are systematically assessing genomic causes of CP in a clinically well-characterised Australian cohort with the aim of developing knowledge and tools for routine clinical diagnosis and to inform personalised care pathways for children with CP. 

Funded by Cerebral Palsy Alliance Research Foundation grant to Dr Mark Corbett and Prof Jozef Gecz

Our research has shown that at least one quarter of CP is caused by rare genetic changes. It is also likely that combinations of genetic variants that are more common in the general population could confer a high risk for CP. Similar combined genetic effects (polygenic risks) are known to contribute to disorders that overlap with CP, including epilepsy. In this project, we are inferring polygenic risk for CP using data from large studies investigating common genetic changes contributing to the risk of known CP risk factors or comorbidities, including premature birth, low birth weight, epilepsy, autism spectrum disorder and cognitive ability.

Funded by Medical Research Future Fund Early and Mid-career Researcher Grant to Dr Clare van Eyk

Despite the broad implementation of massively parallel sequencing, >50% of rare disease patients still remain without a diagnosis after clinical and research testing. This project applies a coordinated multi-institutional, multi-disciplinary approach to rare disease diagnosis, targeting those which remain unresolved due to biological (phenotypic variability, tissue-specific mosaicism and genetic modifiers), analytical (interpretation of variants) or technical (incomplete genomic analysis) factors. Taking advantage of improved bioinformatic pipelines, along with emerging technologies such as long-read genome and transcriptome sequencing and optical genomic mapping, this project aims to end the diagnostic odyssey for patients and their families. Novel mechanisms or genetic loci will be further investigated for pathogenicity utilising a range of functional genomic approaches. For more information, see https://www.australiangenomics.org.au/research/the-rare-disease-collective/