Cerebral palsy may be a trait rather than a disease

Historically, cerebral palsy (CP) was linked largely to events at birth, including prematurity or temporary loss of oxygen to the brain, but research over the past decade has suggested that genetic factors contribute to CP in many children. In a study publishing in the Cell Press journal American Journal of Human Genetics on September 3, researchers report that only 89 of the 515 genes previously linked to CP have a statistically significant association with the condition. They suggest that instead of viewing CP as a single disease with genetic causes, it may be better described as a collection of symptoms that can occur in many different conditions as a result of both genetic variants and environmental factors. 

"There has been a lack of consensus on the definition of cerebral palsy and on the role of genetics in disease pathogenesis, leading to substantial variability in whether a child is diagnosed with CP," says corresponding author Peter Robinson of the Jackson Laboratory for Genomic Medicine and the Berlin Institute of Health at Charité. 

"We have developed a paradigm that considers CP to be a phenotypic trait rather than a precise disease diagnosis. A better understanding of specific genetic variants has the potential to improve our understanding of the biology of the disease." 

CP is the most common motor disability in children, with up to 10,000 babies diagnosed in the United States every year. Unlike many other neuromotor diseases found in children, CP is nonprogressive, meaning that it does not worsen over time. With rehabilitation and physical therapy, many patients can see improvements in their symptoms. 

We decided to do this study because there has been no accepted statistical method to determine if a disease-associated gene is 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." 

Adam Arterbery, first author, Jackson Laboratory for Genomic Medicine

The researchers examined genetic evidence from 21 previously published studies involving 5,440 people diagnosed with CP. Collectively, those studies reported potentially causal variants in a total of 515 genes. But the new analysis found a statistically significant association with CP for only 89 of those 515 genes. 

The team also conducted whole-genome sequencing on 460 children from 453 families who had been diagnosed with CP and treated at Shriners Children's hospitals around the U.S. Genetic variants classified as pathogenic or likely pathogenic were identified in 70 families, involving 60 different genes. Only 16 of those 60 genes overlapped with genes that showed statistically significant evidence of association in the authors' analysis of previously published studies. 

The authors say that their analysis does not rule out a true association of the remaining genes with CP. Rather, it shows that currently, sufficient evidence does not exist to establish a statistically significant association.

Based on their findings, the researchers propose a new way of thinking about CP: instead of viewing it as a single disease with a single set of causes, it may be better understood as a clinical feature that can occur in many different conditions. Under this model, both genetic variants and environmental factors can influence the likelihood of developing the symptoms associated with CP. 

"This framework could improve interpretation of genomic testing, help identify children who may warrant closer CP surveillance or specialist referral, and potentially identify genetic conditions requiring disease-specific management," Robinson says. "But clinical utility and patient benefit will absolutely need validation before these findings can be applied to patient care." 

Further research will focus on building larger patient cohorts, conducting prospective studies of clinical utility and cost-effectiveness, and improving the accessibility of genomic and clinical data. 

"We hope our study will stimulate discussion about CP terminology, gene-disease associations, and variant interpretation," Arterbery says. "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." 

This work was supported by Shriners Children's, the National Institutes of Health (NIH), Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Human Genome Research Institute, and the Alexander von Humboldt Foundation.