CP: To Test or Not to Test?

Source: Lewis SA, Chopra M, Cohen JS, et al. Clinical actionability of genetic findings in cerebral palsy: a systematic review and meta-analysis. JAMA Pediatr. 2025;179(2):137-144; doi: 10.1001/jamapediatrics.2024.5059.Investigators from multiple institutions conducted a systematic review and meta-analysis to estimate the proportion of patients with cerebral palsy (CP) with a pathogenic genetic variant for whom treatment might improve outcomes. A systematic process was used to identify published studies of >10 individuals with CP who received exome sequencing with variant pathogenicity determined based on American College of Medical Genetics guidelines. Patients from the identified studies (research cohort) were combined with a group of individuals with CP who had undergone exome sequencing as part of their clinic care (clinical cohort). The investigators evaluated each pathogenic variant to identify those which were actionable, ie, variants for which a specific treatment was available to either: treat the primary cause of pathology, prevent future triggers that would worsen the condition, or improve at least one symptom of the condition. For each actionable pathogenic variant identified, the investigators assessed the clinical utility of the knowledge of the genetic abnormality using 3 criteria: seriousness of the condition’s natural history, safety and practicality of the available treatment, and potential benefit of the treatment. Each of these criteria was scored on a 0–3 scale, and clinical utility was defined as the sum of the 3 scores, yielding possible scores ranging from 0–9. Ratings and scores from each of the 3 criteria and overall clinical utility from each pathogenic variant were averaged.A total of 496 individuals with CP with exome sequencing were identified from 4 published studies and combined with 1,345 patients in the clinical cohort. Among the total population of 1,841 patients, a pathogenic variant was identified in 502 (27%). There were 243 specific genetic variants, including 94 that affected 2 or more patients; 140 genetic variants were classified as actionable by the investigators. Thus, 140 of the 1,841 study participants (8%) had a genetic abnormality that was potentially amenable to specific treatment. A total of 101 actionable variants were evaluated. The seriousness of the condition associated with the variant was rated as severe in 55, moderate in 43, and mild in 3, for a mean score of 2.40. Safety and practicality of possible treatments were ranked as no or low risk in 24, mild in 48, moderate in 25, and 4 as high-risk (overall score, 1.94). The efficacy of possible treatment was classified as highly effective for 18 variants, moderately effective for 45, and mildly effective for 38, for a mean score of 1.76. The mean overall clinical utility of identifying genetic variants was 6.10, with a range of 3.38 to 9.00.The authors conclude that 8% of patients with CP had a pathogenic genetic variant that was potentially treatable.Dr Badawi has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.The results of this elegant study provide actionable information for clinicians caring for children with a diagnosis of CP. Approximately 3 in 1,000 children have a diagnosis of CP,1 defined by the American Neurological Association as a group of neurological disorders that appear in infancy or early childhood and permanently affect body movement and muscle coordination. The disorder can either be congenital or acquired and, though extreme prematurity and perinatal hypoxia are commonly known causes for congenital CP, there are many risk factors, and the cause often is not known.2,3Therapeutic recommendations typically include physical therapy, occupational therapy, and potentially tone management; however, as the results of this study highlight, advances in genetics are beginning to provide opportunities for precision medicine. Using a measure of clinical utility adapted from the NIH ClinGen rubric, the authors determined that genetic testing could provide actionable information for 8% of children with CP, with another 1% having actionable treatments in development. The highest clinical utility score was noted for preventive measures, indicating the importance of identifying actionable genotypes early.Not all the genetic findings resulted in specific treatment recommendations, and just over half the treatments recommended had level C evidence or above based on the Oxford Centre for Evidence-Based Medicine guidelines. However, the authors note that precision medicine is a rapidly advancing field and that this study did not include other potential benefits of determining a genetic cause for CP such as a family’s desire to identify an etiology, family planning, or access to rare disorder communities.Which children with CP warrant testing? Janzing and colleagues found that strong indicators of a potential genetic etiology were dyskinesia and the absence of spasticity, while the presence of intellectual disability, no preterm birth, and no unilateral distribution of symptoms were moderate indicators.4 A reasonable approach would be to do genetic testing in any child with these indicators, regardless of risk factors for CP, and in any child without a clear risk factor.There are many potential benefits to identifying a genetic etiology for congenital CP, and the clinical utility for treatment is a rapidly advancing field. (See AAP Grand Rounds. 2022;47[5]:56.)5