Researchers using whole-exome sequencing have identified that mutations that disrupt neuritogenesis may confer risk for cerebral palsy.
Cerebral palsy is a neurodevelopmental disorder impacting motor function. It affects ~2-3 per 1,000 children worldwide. Within the first few years of life, children will develop a movement disorder as a manifestation of disrupted brain development. Like other neurodevelopmental disorders, such as autism, no single causative factor has been implicated in cerebral palsy. Several environmental factors, including prematurity, infection, hypoxia-ischemia and stroke, are major contributors to cerebral palsy risk. Estimates suggest that 40% of cerebral palsy is heritable. Nevertheless, up to ~40% of cases do not have a readily identifiable aetiology. Previous analyses have found predicted deleterious copy-number variants in 10-31% of cases.
In a study, published in Nature Genetics, researchers performed whole-exome sequencing of 250 parent-offspring trios. Here, they observed enrichment of damaging de novo mutations in cerebral palsy cases. They found that two genes (TUBA1A and CTNNB1) had multiple damaging de novo mutations and also met genome-wide significance. Additionally, they identified two novel monogenic aetiologies – FBXO31 and RHOB. They found that the RHOB mutation enhanced active-state Rho effector binding, while the FBX031 mutation diminished cyclin D levels. These candidate cerebral palsy risk genes all overlapped with neurodevelopmental disorder genes. They also identified, through network analyses, enrichment of Rho GTPase, extracellular matrix, focal adhesion and cytoskeleton pathways. Therefore, the team predict that disruption of genes involved in neurodevelopmental patterning may alter early neuritogenesis and neuronal functional network connectivity in cerebral palsy.
The team estimated that 14% of cases could be accounted for by an excess of damaging de novo or recessive variants. These findings provide evidence to suggest for genetically-mediated dysregulation of early neuronal connectivity in cerebral palsy. This data along with environmental influencers should be used to assess the aetiology of individual’s cerebral palsy. The team believe this will have important clinical, research and medico-legal implications. They also hope that further insight into genomic mechanisms of cerebral palsy may help guide therapeutic development efforts in an area where novel therapies have not been introduced for decades.
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