Researchers have challenged the long-held view of cerebral palsy (CP) as a single disease, saying the condition may instead be a collection of symptoms caused by different genetic and environmental factors.
The study, published in the American Journal of Human Genetics, found that only 89 of 515 genes previously reported as being linked to cerebral palsy had statistically significant evidence of association with the condition.
The findings suggest that genetics may play an important role in cerebral palsy, but that the condition is more complex than previously understood.
Historically, CP was largely associated with events around birth, particularly premature birth or temporary oxygen deprivation to the brain. However, research over the past decade has increasingly pointed to genetic factors as contributors to the condition in some children.
Researchers from the Jackson Laboratory for Genomic Medicine and the Berlin Institute of Health at Charité said there has been no widely accepted statistical approach for determining whether genes previously associated with CP are genuinely linked to the condition.
“We have developed a paradigm that considers CP to be a phenotypic trait rather than a precise disease diagnosis,” said corresponding author Peter Robinson.
“A better understanding of specific genetic variants has the potential to improve our understanding of the biology of the disease.”
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The researchers reviewed genetic evidence from 21 previously published studies involving 5,440 people diagnosed with cerebral palsy.
Those studies collectively identified potentially causal genetic variants in 515 genes. However, the new analysis found statistically significant evidence of an association with CP for only 89 of the genes.
The researchers stressed that the remaining genes cannot be dismissed as unrelated to CP. Rather, there is currently insufficient statistical evidence to establish a significant association.
The team also carried out whole-genome sequencing on 460 children from 453 families diagnosed with CP and treated at Shriners Children’s hospitals across the United States.
Pathogenic or likely pathogenic genetic variants were identified in 70 families, involving 60 different genes. However, only 16 of those 60 genes overlapped with the genes that had significant evidence of association in the researchers’ analysis of previous studies.
First author Adam Arterbery said the study was undertaken partly because of the lack of an accepted statistical method for determining whether disease-associated genes are truly linked to CP.
“We discovered it was extremely difficult to find statistical evidence of causality for many of the genetic variants previously linked to CP,” he said.
Cerebral palsy is the most common motor disability in children. It affects movement and posture and is non-progressive, meaning the underlying condition does not worsen over time.
With rehabilitation and physical therapy, many children can improve their movement and other symptoms.
The researchers propose that CP should be viewed less as a single disease and more as a clinical feature that can occur in several different conditions.
Under this approach, both genetic variants and environmental factors may contribute to the development of symptoms associated with CP.
Robinson said the new framework could eventually improve how genetic test results are interpreted and help doctors identify children who may require closer monitoring or referral to specialists. It could also help identify children with genetic conditions that require specific treatment.
However, he cautioned that the findings are not yet ready for routine clinical use.
“Clinical utility and patient benefit will absolutely need validation before these findings can be applied to patient care,” he said.
The researchers said future studies will focus on building larger patient groups, conducting prospective studies to determine the clinical usefulness and cost-effectiveness of genetic testing, and improving access to genomic and clinical data.
Arterbery said the researchers hope the findings will encourage further discussion about the terminology used to describe CP, gene-disease associations, and how genetic variants are interpreted.
“The most productive response will be further validation and development of better genotype-phenotype evidence rather than treating the findings as a definitive list of CP genes,” he said.
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