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

Abstract

ImportanceExome 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.ObjectiveTo evaluate if the diagnostic yield of exome or genome sequencing in cerebral palsy is similar to that of other neurodevelopmental disorders.Data SourcesThe study team searched PubMed for studies published between 2013 and 2022 using cerebral palsy and genetic testing terms. Data were analyzed during March 2022.Study SelectionStudies 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 Extraction and SynthesisData 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.Main Outcomes and MeasuresThe 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.ResultsThirteen 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%).Conclusions and RelevanceIn 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.

All Patients With a Cerebral Palsy Diagnosis Merit Genomic Sequencing

“…Early genomic testing in these patients, irrespective of initial clinical diagnosis, can prevent a diagnostic odyssey, with more than half of individuals for whom data were available undergoing a targeted single gene or gene panel before eventually receiving a diagnosis from exome or genome sequencing . As the article by Gonzalez-Mantilla et al concludes, these data provide sufficient evidence to support the inclusion of genomic sequencing as a first-tier test for individuals with cerebral palsy, regardless of their comorbidities and risk factors.…”

“…However, imaging alone will often not provide an accurate etiological diagnosis and may miss the presence of dual etiologies . The meta-analysis by Gonzalez-Mantilla et al reports on 13 studies totaling 2612 individuals with cerebral palsy and conservatively shows that the diagnostic yield of exome or genome sequencing was 31.1%. This is likely to be an underestimate, as not all studies cast a wider genetic net to look for copy number variation and many did not conduct parent-child trio analysis.…”

“…The published meta-analysis provides strong data to justify the cost of genomic sequencing. The diagnostic yield for cerebral palsy is similar to other neurodevelopmental disorders, such as developmental delay, intellectual disability, and autism spectrum disorder, where genomic sequencing has been largely accepted as a first-tier test.…”

“…The genetic causes of cerebral palsy are highly heterogeneous, with both meta-analyses (of mostly the same cohorts) finding that the most frequent genetic cause, variation in CTNNB1 , still only accounted for 4% of monogenic cases. Children with CTNNB1 neurodevelopmental disorder have a relatively homogeneous clinical presentation, with frequent truncal hypotonia and nonprogressive peripheral spasticity or hypertonia .…”

Implications of Genetic Variants in Cerebral Palsy

“…The disconnect has greatly contributed to protracted litigation with experts of varying degrees of professional stature espousing completely contradictory opinions. Gonzalez-Mantilla et al have rigorously collated the literature and reported that whole exome sequencing (WES) studies found abnormalities in 31% of CP cases. In an accompanying editorial, Van Eyk et al suggested that WES should be performed for all CP cases.…”