Clinical actionability of genetic findings in cerebral palsy

Abstract

ABSTRACTBackground and objectivesSingle gene mutations are increasingly recognized as causes of cerebral palsy (CP) phenotypes, yet there is currently no standardized framework for measuring their clinical impact. We evaluated Pathogenic/Likely Pathogenic (P/LP) variants identified in individuals with CP to determine how frequently genetic testing results would prompt changes in care.MethodsWe analyzed published P/LP variants in OMIM genes identified in clinical (n = 1,345 individuals) or research (n = 496) cohorts using exome sequencing of CP patients. We established a working group of clinical and research geneticists, developmental pediatricians, genetic counselors, and neurologists and performed a systematic review of existing literature for evidence of clinical management approaches linked to genetic disorders. Scoring rubrics were adapted, and a modified Delphi approach was used to build consensus and establish the anticipated impact on patient care. Overallclinical utilitywas calculated from metrics assessingoutcome severityif left untreated,safety/practicalityof the intervention, and anticipated interventionefficacy.ResultsWe found 140/1,841 (8%) of individuals in published CP cohorts had a genetic diagnosis classified asactionable, defined as prompting a change in clinical management based on knowledge related to the genetic etiology. 58/243 genes with P/LP variants were classified as actionable; 16 had treatment options targeting theprimary disease mechanism, 16 hadspecific prevention strategies, and 26 hadspecific symptom managementrecommendations. The level of evidence was also graded according to ClinGen criteria; 44.6% of interventions had evidence class “D” or below. The potential interventions haveclinical utilitywith 97% of outcomes being moderate-highseverityif left untreated and 62% of interventions predicted to be of moderate-highefficacy. Most interventions (71%) were considered moderate-highsafety/practicality.DiscussionOur findings indicate that actionable genetic findings occur in 8% of individuals referred for genetic testing with CP. Evaluation of potentialefficacy, outcomeseverity, and interventionsafety/practicalityindicates moderate-highclinical utilityof these genetic findings. Thus, genetic sequencing to identify these individuals for precision medicine interventions could improve outcomes and provide clinical benefit to individuals with CP. The relatively limited evidence base for most interventions underscores the need for additional research.