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Cerebral Palsy Genomic Study Points to Rare Damaging Mutations as Disease Contributors

NEW YORK – Up to 14 percent of cerebral palsy cases could be attributed to damaging de novo mutations or recessive variants, according to a new study published in Nature Genetics on Monday.

In order to determine whether genomic factors may underlie cerebral palsy — along with the well-known environmental factors, such as prematurity, infection, hypoxia-ischemia, and pre- and perinatal stroke — an international team of researchers performed whole-exome sequencing on 250 cerebral palsy parent-offspring trios. They observed an enrichment of damaging de novo mutations in the cases, including in eight genes with multiple damaging de novo mutations. Two of these genes, TUBA1A and CTNNB1, met genome-wide significance.

The researchers also noted that candidate risk genes overlapped with neurodevelopmental disorder genes, and their network analyses identified an enrichment of Rho GTPase, extracellular matrix, focal adhesion, and cytoskeleton pathways. Risk genes in these pathways were shown to regulate neuromotor function in a Drosophila reverse genetics screen. The findings provided evidence for genetically mediated dysregulation of early neuronal connectivity in cerebral palsy.

For their analysis, the researchers compared the exomes of 250 cerebral palsy family trios with those of 1,789 control trios. They found an enrichment of damaging mutations in cerebral palsy cases, with "damaging" being defined as loss-of-function, missense, or deleterious variants.

They also found that nearly 12 percent of the cerebral palsy cases in their cohort could be attributed to an excess of damaging de novo mutations, and that there was greater enrichment of damaging mutations in idiopathic compared to environmental cerebral palsy cases.

Next, the researchers identified eight genes harboring two or more damaging de novo mutations. The gene-level enrichment of protein-damaging mutations in two of these genes, TUBA1A and CTNNB, strongly implicated them as bona fide cerebral palsy-associated genes, they wrote. Further, four of the eight genes, ATL1, CTNNB1, SPAST, and TUBA1A, have previously been associated with human cerebral palsy phenotypes.

They also identified damaging de novo mutations in RHOB and FBXO31. RHOB is known to control dendritic spine outgrowth but has not previously been associated with a human disease. FBXO31 is known to control axonal outgrowth and is essential for dendrite growth and neuronal migration in the developing brain.

The researcher also sought to determine the overlap between genes harboring rare damaging variants from their cerebral palsy cohort with known neurodevelopmental disorder risk genes and found substantial overlap between their cerebral palsy candidate gene list and disorders such as epilepsy, autism spectrum disorder, or intellectual disability. In contrast, there was no such overlap with Alzheimer's disease.

A total of 28.9 percent of cerebral palsy risk genes overlapped with genes linked to intellectual disability, 11.1 percent with genes involved in epilepsy, and 6.3 percent with genes implicated in autism spectrum disorder. There was also overlap with genes involved in other genetic neurodevelopmental disorders, indicating potential genetic pleiotropy and common etiologies of such co-occurring disorders.

"The cohort-wide enrichment of [de novo mutations] we detected is consistent with the observation that most cases of [cerebral palsy] occur sporadically," the authors wrote, adding that they estimate 75 genes to contribute to cerebral palsy through a de novo mechanism.

"Conservatively, we estimate that 14 percent of the cases in our cohort can be accounted for by damaging genomic variants," they wrote, as compared to birth-related hypoxia-ischemia, which is estimated to be involved in about 6 percent of cerebral palsy cases. This, they added, indicates "that genomic mutations represent an important, independent contributor to [cerebral palsy] etiology that historically has been overlooked."