TY - JOUR
T1 - Molecular Diagnostic Yield of Exome Sequencing and Chromosomal Microarray in Cerebral Palsy
T2 - A Systematic Review and Meta-analysis
AU - Srivastava, Siddharth
AU - Lewis, Sara A.
AU - Cohen, Julie S.
AU - Zhang, Bo
AU - Aravamuthan, Bhooma R.
AU - Chopra, Maya
AU - Sahin, Mustafa
AU - Kruer, Michael C.
AU - Poduri, Annapurna
N1 - Funding Information:
Funding/Support: This study was supported by grants 1K23NS119666 (Dr Srivastava), 1K08NS117850-01A1 (Dr Aravamuthan), and 1R01NS106298 (Dr Kruer), from the National Institute of Health/National Institute of Neurological Disorders and Stroke; grant 1R01DK123113 from the National Institute of Health/ National Institute of Digestive & Kidney Diseases (Dr Kruer); financial support from the Cerebral Palsy Alliance Research Foundation, CureCP, PTC Therapeutics, and BridgeBio (Dr Kruer); and educational support from Medtronic (Dr Kruer).
Publisher Copyright:
© 2022 American Medical Association. All rights reserved.
PY - 2022/12/12
Y1 - 2022/12/12
N2 - 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..
AB - 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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U2 - 10.1001/jamaneurol.2022.3549
DO - 10.1001/jamaneurol.2022.3549
M3 - Article
C2 - 36279113
AN - SCOPUS:85141053503
SN - 2168-6149
VL - 79
SP - 1287
EP - 1295
JO - JAMA Neurology
JF - JAMA Neurology
IS - 12
ER -