Diagnostic Yield of Exome Sequencing in Cerebral Palsy and Implications for Genetic Testing Guidelines

Abstract

Exome sequencing is a first-tier diagnostic test for individuals with neurodevelopmental disorders, including intellectual disability/developmental delay and autism spectrum disorder; however, this recommendation does not include cerebral palsy. To evaluate if the diagnostic yield of exome or genome sequencing in cerebral palsy is similar to that of other neurodevelopmental disorders. The study team searched PubMed for studies published between 2013 and 2022 using cerebral palsy and genetic testing terms. Data were analyzed during March 2022. Studies performing exome or genome sequencing in at least 10 participants with cerebral palsy were included. Studies with fewer than 10 individuals and studies reporting variants detected by other genetic tests were excluded. Consensus review was performed. The initial search identified 148 studies, of which 13 met inclusion criteria. Data were extracted by 2 investigators and pooled using a random-effects meta-analysis. Incidence rates with corresponding 95% CIs and prediction intervals were calculated. Publication bias was evaluated by the Egger test. Variability between included studies was assessed via heterogeneity tests using the I2 statistic. The primary outcome was the pooled diagnostic yield (rate of pathogenic/likely pathogenic variants) across studies. Subgroup analyses were performed based on population age and on the use of exclusion criteria for patient selection. Thirteen studies were included consisting of 2612 individuals with cerebral palsy. The overall diagnostic yield was 31.1% (95% CI, 24.2%-38.6%; I2 = 91%). The yield was higher in pediatric populations (34.8%; 95% CI, 28.3%-41.5%) than adult populations (26.9%; 95% CI, 1.2%-68.8%) and higher among studies that used exclusion criteria for patient selection (42.1%; 95% CI, 36.0%-48.2%) than those that did not (20.7%; 95% CI, 12.3%-30.5%). In this systematic review and meta-analysis, the genetic diagnostic yield in cerebral palsy was similar to that of other neurodevelopmental disorders for which exome sequencing is recommended as standard of care. Data from this meta-analysis provide evidence to support the inclusion of cerebral palsy in the current recommendation of exome sequencing in the diagnostic evaluation of individuals with neurodevelopmental disorders.