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Meta-Analysis
. 2023 May 1;177(5):472-478.
doi: 10.1001/jamapediatrics.2023.0008.

Diagnostic Yield of Exome Sequencing in Cerebral Palsy and Implications for Genetic Testing Guidelines: A Systematic Review and Meta-analysis

Pedro J Gonzalez-Mantilla  1 , Yirui Hu  2 , Scott M Myers  1 , Brenda M Finucane  1 , David H Ledbetter  3 , Christa L Martin  1 , Andres Moreno-De-Luca  1   4   5
Affiliations
Meta-Analysis

Diagnostic Yield of Exome Sequencing in Cerebral Palsy and Implications for Genetic Testing Guidelines: A Systematic Review and Meta-analysis

Pedro J Gonzalez-Mantilla et al. JAMA Pediatr. .

Abstract

Importance: 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.

Objective: To evaluate if the diagnostic yield of exome or genome sequencing in cerebral palsy is similar to that of other neurodevelopmental disorders.

Data sources: 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.

Study selection: 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 extraction and synthesis: 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.

Main outcomes and measures: 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.

Results: 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%).

Conclusions and relevance: 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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Gonzalez-Mantilla reported grants from the Eunice Kennedy Shriver National Institute of Child Health & Human Development (R01HD104938-01A1) during the conduct of the study and grants from the National Institute of Mental Health (R01MH074090) outside the submitted work. Dr Myers reported grants from the Eunice Kennedy Shriver National Institute of Child Health & Human Development (R01HD104938-01A1) during the conduct of the study and grants from the National Institutes of Health/National Institute of Mental Health (2R01MH074090) outside the submitted work. Dr Finucane reported grants from the National Institutes of Health (R01MH074090) during the conduct of the study. Dr Ledbetter reported grants from the National Institutes of Health/National Institute of Mental Health (2R01MH074090), personal fees from Natera, is a scientific consultant to Natera, MyOme, Singular Genomics, Nest Genomics, and X-Therma outside the submitted work, and is an employee of Unified Patient Network. Dr Martin reported grants from the National Institutes of Health/National Institute of Mental Health (R01HD104938) during the conduct of the study and grants from the National Institutes of Health/National Institute of Mental Health (R01MH074090 and U01MH119705) and from the National Institutes of Health/National Human Genome Research Institute (U41HG006834) outside the submitted work. Dr Moreno-De-Luca reported grants from the Eunice Kennedy Shriver National Institute of Child Health & Human Development (R01HD104938) during the conduct of the study and grants from the National Institute of Mental Health (R01MH074090) outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Flowchart of Study Selection
CMA indicates chromosomal microarray analysis; CP, cerebral palsy; ES, exome sequencing; GPS, gene panel sequencing; GS, genome sequencing; NDD, neurodevelopmental disorders; SNV, single-nucleotide variants.
Figure 2.
Figure 2.. Forest Plot of Diagnostic Yield of Exome or Genome Sequencing in Cerebral Palsy Studies
Dx indicates diagnositic; P/LP, pathogenic/likely pathogenic.
See this image and copyright information in PMC

Comment in

References

    1. Moreno-De-Luca A, Myers SM, Challman TD, Moreno-De-Luca D, Evans DW, Ledbetter DH. Developmental brain dysfunction: revival and expansion of old concepts based on new genetic evidence. Lancet Neurol. 2013;12(4):406-414. doi:10.1016/S1474-4422(13)70011-5 - DOI - PMC - PubMed
    1. Rosenbaum P, Paneth N, Leviton A, et al. . A report: the definition and classification of cerebral palsy April 2006. Dev Med Child Neurol Suppl. 2007;109(s109):8-14. doi:10.1111/j.1469-8749.2007.tb12610.x - DOI - PubMed
    1. Smithers-Sheedy H, Badawi N, Blair E, et al. . What constitutes cerebral palsy in the twenty-first century? Dev Med Child Neurol. 2014;56(4):323-328. doi:10.1111/dmcn.12262 - DOI - PubMed
    1. Oskoui M, Coutinho F, Dykeman J, Jetté N, Pringsheim T. An update on the prevalence of cerebral palsy: a systematic review and meta-analysis. Dev Med Child Neurol. 2013;55(6):509-519. doi:10.1111/dmcn.12080 - DOI - PubMed
    1. McGuire DO, Tian LH, Yeargin-Allsopp M, Dowling NF, Christensen DL. Prevalence of cerebral palsy, intellectual disability, hearing loss, and blindness, National Health Interview Survey, 2009-2016. Disabil Health J. 2019;12(3):443-451. doi:10.1016/j.dhjo.2019.01.005 - DOI - PMC - PubMed

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