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Meta-Analysis
. 2022 Dec 1;79(12):1287-1295.
doi: 10.1001/jamaneurol.2022.3549.

Molecular Diagnostic Yield of Exome Sequencing and Chromosomal Microarray in Cerebral Palsy: A Systematic Review and Meta-analysis

Siddharth Srivastava  1 , Sara A Lewis  2   3   4   5   6 , Julie S Cohen  7   8 , Bo Zhang  1 , Bhooma R Aravamuthan  9 , Maya Chopra  1 , Mustafa Sahin  1 , Michael C Kruer  2   3   4   5   6 , Annapurna Poduri  1   10
Affiliations
Meta-Analysis

Molecular Diagnostic Yield of Exome Sequencing and Chromosomal Microarray in Cerebral Palsy: A Systematic Review and Meta-analysis

Siddharth Srivastava et al. JAMA Neurol. .

Abstract

Importance: There are many known acquired risk factors for cerebral palsy (CP), but in some cases, CP is evident without risk factors (cryptogenic CP). Early CP cohort studies report a wide range of diagnostic yields for sequence variants assessed by exome sequencing (ES) and copy number variants (CNVs) assessed by chromosomal microarray (CMA).

Objective: To synthesize the emerging CP genetics literature and address the question of what percentage of individuals with CP have a genetic disorder via ES and CMA.

Data sources: Searched articles were indexed by PubMed with relevant queries pertaining to CP and ES/CMA (query date, March 15, 2022).

Study selection: Inclusion criteria were as follows: primary research study, case series with 10 or more nonrelated individuals, CP diagnosis, and ES and/or CMA data used for genetic evaluation. Nonblinded review was performed.

Data extraction and synthesis: Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were used for assessing data quality and validity. Data were extracted by a single observer.

Main outcomes and measures: A separate meta-analysis was performed for each modality (ES, CMA). The primary outcome was proportion/molecular diagnostic yield (number of patients with a discovered genetic disorder divided by the total number of patients in the cohort), evaluated via meta-analysis of single proportions using random-effects logistic regression. A subgroup meta-analysis was conducted, using risk factor classification as a subgroup. A forest plot was used to display diagnostic yields of individual studies.

Results: In the meta-analysis of ES yield in CP, the overall diagnostic yield of ES among the cohorts (15 study cohorts comprising 2419 individuals from 11 articles) was 23% (95% CI, 15%-34%). The diagnostic yield across cryptogenic CP cohorts was 35% (95% CI, 27%-45%), compared with 7% (95% CI, 4%-12%) across cohorts with known risk factors (noncryptogenic CP). In the meta-analysis of CMA yield in CP, the diagnostic yield of CMA among the cohorts (5 study cohorts comprising 294 individuals from 5 articles) was 5% (95% CI, 2%-12%).

Conclusions and relevance: Results of this systematic review and meta-analysis suggest that for individuals with cryptogenic CP, ES followed by CMA to identify molecular disorders may be warranted.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Srivastava reported receiving consulting fees from GLG Research, Guidepoint, Novartis, ExpertConnect, and Orchard Therapeutics outside the submitted work. Dr Cohen reported receiving consulting fees from Invitae, PTC Therapeutics, and Illumina outside the submitted work. Dr Aravamuthan reported receiving consulting fees from Neurocrine Biosciences and UpToDate outside the submitted work. Dr Sahin reported receiving grants from Roche, Novartis, Biogen, Astellas, Aeovian, Bridgebio, Aucta, and Quadrant Biosciences outside the submitted work. Dr Kruer reported receiving grants from PTC Therapeutics and Medtronic; consultant fees from PTC Therapeutics, Merz, Bridge Bio, the Ontario Brain Institute, the US National Health Research Services Administration, the Department of Defense, and Neurocrine Biosciences; and scientific advisory fees from Aeglea and Merz outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Articles Included and Excluded in the Meta-analysis of Exome Sequencing and Chromosomal Microarray for Cerebral Palsy
A, Search queries for the articles included and excluded in exome sequencing for cerebral palsy include "cerebral palsy" AND "exome sequencing" OR "next-generation sequencing.” B, Search queries included and excluded in chromosomal microarray for cerebral palsy include “copy number” OR “microarray” OR “deletion” OR “duplication” OR “chromosomal rearrangement."
Figure 2.
Figure 2.. Forest Plot Showing Overall Diagnostic Yield Stratified by Cerebral Palsy (CP) Risk Factor Classification
Overall diagnostic yield of exome sequencing (A) and chromosomal microarray (B).
Figure 3.
Figure 3.. Genetic Disorders Identified by Exome Sequencing That Occurred in More Than 5 Individuals Across Study Cohorts
Figure 4.
Figure 4.. Proposed Framework for the Genetic Evaluation of an Individual With Cerebral Palsy (CP)
aRed flags raising the possibility of a genetic disorder include: absence of perinatal risk factors; consanguinity; more than 1 affected family member; progressive or regressive course (not initially apparent but eventually apparent after the diagnosis of CP); presence of congenital anomalies; dysmorphic features; normal brain magnetic resonance imaging (MRI) findings; unexplained biochemical/metabolic disturbances; and mismatch between perinatal history, brain MRI, and motor phenotype/severity (such as prematurity at 36 weeks with minimal neonatal intensive care course yet severe spasticity and intellectual disability; globus pallidus signal changes yet spastic diplegia phenotype). Diagnosis may lead to further action, such as enrollment in research registries and/or clinical trials, genetic counseling, and specific management changes. CMA indicates chromosomal microarray; CNV, copy number variant; ES, exome sequencing; WGS, whole-genome sequencing.
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