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Genetic Variants May Contribute to Cerebral Palsy

April 10, 2024
in General
Genetic Variants May Contribute to Cerebral Palsy
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A large study analyzing the DNA of children with cerebral palsy has found a high prevalence of genomic variation that likely contributes to the risk of developing the condition.

The investigators performed whole-genome sequencing in 327 children with cerebral palsy and their biological parents, as well as two pediatric control cohorts. They found that 11.3% of the children with cerebral palsy had a genomic variation that likely contributed to their risk for developing the condition. Another 17.7% had variants of uncertain significance.

photo of Darcy FehlingsDarcy Fehlings, MD

“That’s quite high, and it tells us that genetic risk is something that we need to think about when we’re doing a workup for children with cerebral palsy,” study author Darcy Fehlings, MD, senior clinician scientist at Holland Bloorview Kids Rehabilitation Hospital and professor of pediatrics at the University of Toronto in Ontario, told Medscape Medical News.

The study was published on March 29, 2024, in Nature Genetics.

Whole-Genome Sequencing

Cerebral palsy is the most common physical disability with childhood onset. The neuromotor disability occurs when the developing brain is damaged, but genetic factors are increasingly recognized. Many of the genes identified in this study are involved in the early development of the brain.

The study used whole-genome sequencing with data prospectively collected at 11 sites across Canada. “It’s basically the best probe we have right now for looking at genetic contribution,” said Fehlings. The advanced technique is more sensitive than other tests, such as exome sequencing, which analyzes the protein-coding regions of genes only.

To further improve their analysis, the investigators analyzed samples from the biological parents of the children with cerebral palsy. The “trio data,” which included samples from the child and both biological parents, allowed researchers to determine whether the genetic variation was inherited or a newly developed de novo change. The findings showed a high prevalence of de novo variations, which are more likely to cause complications. The investigators also included two control cohorts of children without cerebral palsy. Comparing to these populations “gives us more information on the clinical importance of these genes,” according to Fehlings.

In an approach that distinguished the work from previous research, the investigators analyzed mitochondrial DNA, which is involved in energy production and inherited differently than typical nuclear DNA. They found mitochondria mutations that contributed to neurologic presentation in 1.5% of the study cohort. “We also should think about looking at the mitochondrial function” in research and clinical settings, said Fehlings.

Precision Health

Fehlings emphasized that the study’s findings have clinical relevance. They could potentially inform treatment plans and counseling for families. “This is a really nice opportunity to bring precision health to cerebral palsy,” she said.

Genetic testing may be able to provide a more specific diagnosis for some children. For example, one child in the study was misdiagnosed and found to have dopa-responsive dystonia, which can significantly improve with L-dopa treatment. “That’s a game-changer for the child,” said Fehlings.

Understanding whether variants are inherited can also improve family counseling. “Many parents want to understand why their child has developed cerebral palsy,” said Fehlings. Getting information on the genetic contribution can help demystify the condition.

In the future, Fehlings; Stephen Scherer, PhD, chief of research at the Hospital for Sick Children in Toronto; and Maryam Oskoui, MD, associate professor of pediatrics, neurology, and neurosurgery at McGill University in Montreal, Canada, would like to continue the work with a larger, international cohort. She also hopes the research will fuel interest in translational science aimed at developing new treatments.

Methodological Rigor

Commenting on the study for Medscape Medical News, Steven Miller, MD, head of pediatrics at the University of British Columbia in Vancouver, said that the research is important for improving the care of children with cerebral palsy. “The methodologic strengths of this study position these findings to be impactful for clinical care and next research directions.”

photo of Steven MillerSteven Miller, MD

Miller, who did not participate in the research, is excited to move toward a recognition that, for many children, cerebral palsy “sits at the intersection of inherited and acquired disorders.” Understanding that an underlying genetic predisposition may exist has implications for how providers monitor children with cerebral palsy and counsel families, including during subsequent pregnancies.

Eventually, Miller would like to see more research seeking to understand the links between genetic and environmental exposures. Other next steps could include investigating how genetic changes contribute to acquired brain injuries, “either directly or as a modifier of the response of the brain.” However, Miller emphasized that it is important to consult with patients and their families when determining future research areas.

The study was supported by the Childhood Cerebral Palsy Neuroscience Discovery Network (CP-NET) of the Ontario Brain Institute, Canadian Institutes of Health Research, the Research Foundation of the Cerebral Palsy Alliance, Debbie and Don Morrison, and the University of Toronto McLaughlin Centre. Fehlings reported no relevant financial relationships. Miller reports serving on the leadership of CP-NET. 

Gwendolyn Rak is a health reporter for Medscape based in Brooklyn, New York. 

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Copyright for syndicated content belongs to the linked Source : Medscape – https://www.medscape.com/viewarticle/genetic-variants-may-contribute-cerebral-palsy-2024a10006p2

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