New Study Challenges Genetic Evidence for Cerebral Palsy

Cerebral palsy is the leading cause of physical disability in childhood, affecting up to three in every 1,000 children born worldwide each year.

Yet, despite how widespread cerebral palsy is, scientists have not reached full agreement about either its origins or precisely how the condition should be defined.

Cerebral palsy causes and genetic evidence

Traditionally, this movement disorder has been linked to problems around the time of birth, such as premature birth, infection and oxygen deprivation.

More recently, however, other theories have gained attention. Several studies have proposed that cerebral palsy could be a genetic disorder associated with pathogenic variants in individual genes.

A new study in the American Journal of Human Genetics indicates that the picture may be considerably more complex.

"We wanted to determine how strong the evidence really is linking specific genes to cerebral palsy," researchers Peter Robinson and Adam Arterbery from the Jackson Laboratory for Genomic Medicine in Farmington, Connecticut told ScienceAlert via email.

"We expected that some genes reported as causal for cerebral palsy would have stronger evidence than others, and that a more systematic analysis would distinguish well-supported associations from potentially incidental findings."

Robinson, a computational biologist, and Arterbery, a biocuration researcher in Robinson's laboratory and among the first authors of the paper, carried out an extensive review of the existing research with their team.

They assessed 21 published genetic studies of cerebral palsy and found 515 genes that had previously been suggested as possible causes of the condition.

The team then broadened its search to examine evidence for disease-causing gene mutations across more than 5,500 further studies. Using statistical methods, they evaluated which of the 515 genes previously connected with cerebral palsy could realistically be linked to the condition.

What the cerebral palsy gene analysis found

The findings revealed a substantial gap in the available evidence.

"The magnitude of the discrepancy became striking when we found that only 89 of the 515 genes previously reported as causal in cerebral palsy had sufficient statistical evidence for cerebral palsy association," Robinson and Arterbery told ScienceAlert.

During a separate part of the research, the scientists used whole-genome sequencing for 460 children with cerebral palsy. They detected pathogenic or likely pathogenic variants across 60 genes in roughly 16 percent of the children.

However, according to the team's review of the literature, just 16 of those 60 genes had significant evidence supporting an association with cerebral palsy.

Put another way, genetic tests may identify many gene variants in children who have cerebral palsy, but the researchers say some earlier proposed genetic connections may not represent a genuine disease-causing process.

Instead, the team suggests cerebral palsy may not be one disease or one genetic disorder. It may, rather, describe a group of symptoms that occur alongside, or overlap with, other conditions.

Cerebral palsy as a feature of Mendelian diseases

"We propose here that cerebral palsy can best be understood as a feature of certain Mendelian diseases rather than a separate disease," the researchers write in their paper.

"Our approach is based on a paradigm that considers cerebral palsy to be a disease component (phenotypic feature) rather than a precise disease diagnosis."

The researchers stress that their findings do not show that the hundreds of gene variants in question are unrelated to cerebral palsy, or that they cannot cause it.

Rather, their analysis indicates that the present evidence for many of these candidates is insufficient. Exploring the ways cerebral palsy may overlap with other diseases could therefore offer a more useful route to identifying the origins of its different symptoms.

"We are excited about the possibility of moving beyond simply identifying genetic variants toward understanding how genotype, phenotype and disease mechanisms fit together," the researchers said.

"This could improve the interpretation of genomic testing and ultimately help identify patients who may benefit from more precise evaluation and care."

The findings are reported in the American Journal of Human Genetics.