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Peer-reviewedCC BY 4.0International Journal of Molecular Sciences

Diagnostic Yield and Clinical Actionability of Genetic Testing in Neurodevelopmental Disorders: A Systematic Review and Meta-Analysis

  • Alexandra Aurora Dumitra1,2
  • Ioana Streață2,3
  • Adina Turcu-Știolică4
  • Anca Lelia Riza2,3
  • Rebecca Cristiana Șerban2,3
  • Mihai Gabriel Cucu2,3
  • Alexandru Mihai Prică1
  • Florin Burada2,3
4 affiliations
  1. 1Doctoral School, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
  2. 2Regional Centre of Medical Genetics Dolj, Emergency County Hospital Craiova, 200642 Craiova, Romania
  3. 3Human Genomics Laboratory, Research Center for Gastroenterology and Hepatology (CCGH), University of Medicine and Pharmacy of Craiova, 200638 Craiova, Romania
  4. 4Department of Pharmacoeconomics, Faculty of Pharmacy, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
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Abstract

Genetic testing is increasingly central to the evaluation of neurodevelopmental disorders (NDDs), yet most evidence emphasises diagnostic yield rather than whether findings change clinical care. We conducted a systematic review and meta-analysis (Preferred Reporting Items for Systematic Reviews and Meta-Analyses [PRISMA] 2020) of genetic testing across the diagnostic pathway in NDD populations, focusing on autism spectrum disorder (ASD), intellectual disability, and global developmental delay, to quantify pooled diagnostic yield and clinical actionability. A systematic search of PubMed and Web of Science, with an expanded population and outcome term set, was completed on 1 October 2026, supplemented by an artificial intelligence (AI)-assisted search (Undermind) and reference-list screening. Twenty-three studies were included in a qualitative synthesis and 22 in a quantitative meta-analysis of diagnostic yield (N = 7641 patients tested; diagnostic-yield analysis comprised 23 data points, as Charouf et al. contributed separate whole-exome sequencing (WES) and whole-genome sequencing (WGS) cohorts). Single-proportion random-effects meta-analysis with the Freeman–Tukey double arcsine transformation produced a pooled diagnostic yield of 28% (95% confidence interval [CI] 21–35%; I2 = 96.1%) and pooled clinical actionability of 58% (95% CI 44–72%; I2 = 95.7%) across 16 studies (N = 1538 patients with confirmed diagnoses). A significant yield gradient was observed across modalities (chromosomal microarray analysis [CMA], 16%; WES, 36%; WGS, 43%; p < 0.0001). Actionability estimates were robust across sensitivity analyses (54–64%). Genetic testing in NDDs functions not only as an etiological tool but as an input to personalised management, including pharmacological optimisation, comorbidity surveillance, and resolution of the diagnostic odyssey, albeit with very low certainty of evidence per Grading of Recommendations, Assessment, Development and Evaluations (GRADE), reflecting substantial heterogeneity and observational study design.

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Cite

BibTeXRIS
BibTeX
@article{dumitra2026diagnostic,
  title = {{Diagnostic Yield and Clinical Actionability of Genetic Testing in Neurodevelopmental Disorders: A Systematic Review and Meta-Analysis}},
  author = {Alexandra Aurora Dumitra and Ioana Streață and Adina Turcu-Știolică and Anca Lelia Riza and Rebecca Cristiana Șerban and Mihai Gabriel Cucu and Alexandru Mihai Prică and Florin Burada},
  journal = {International Journal of Molecular Sciences},
  year = {2026},
  month = oct,
  doi = {10.3390/ijms27209113},
  url = {https://www.mdpi.com/1422-0067/27/20/9113},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Diagnostic Yield and Clinical Actionability of Genetic Testing in Neurodevelopmental Disorders: A Systematic Review and Meta-Analysis
AU  - Alexandra Aurora Dumitra
AU  - Ioana Streață
AU  - Adina Turcu-Știolică
AU  - Anca Lelia Riza
AU  - Rebecca Cristiana Șerban
AU  - Mihai Gabriel Cucu
AU  - Alexandru Mihai Prică
AU  - Florin Burada
PY  - 2026
DA  - 2026/10/01
JO  - International Journal of Molecular Sciences
DO  - 10.3390/ijms27209113
UR  - https://www.mdpi.com/1422-0067/27/20/9113
AB  - Genetic testing is increasingly central to the evaluation of neurodevelopmental disorders (NDDs), yet most evidence emphasises diagnostic yield rather than whether findings change clinical care. We conducted a systematic review and meta-analysis (Preferred Reporting Items for Systematic Reviews and Meta-Analyses [PRISMA] 2020) of genetic testing across the diagnostic pathway in NDD populations, focusing on autism spectrum disorder (ASD), intellectual disability, and global developmental delay, to quantify pooled diagnostic yield and clinical actionability. A systematic search of PubMed and Web of Science, with an expanded population and outcome term set, was completed on 1 October 2026, supplemented by an artificial intelligence (AI)-assisted search (Undermind) and reference-list screening. Twenty-three studies were included in a qualitative synthesis and 22 in a quantitative meta-analysis of diagnostic yield (N = 7641 patients tested; diagnostic-yield analysis comprised 23 data points, as Charouf et al. contributed separate whole-exome sequencing (WES) and whole-genome sequencing (WGS) cohorts). Single-proportion random-effects meta-analysis with the Freeman–Tukey double arcsine transformation produced a pooled diagnostic yield of 28% (95% confidence interval [CI] 21–35%; I2 = 96.1%) and pooled clinical actionability of 58% (95% CI 44–72%; I2 = 95.7%) across 16 studies (N = 1538 patients with confirmed diagnoses). A significant yield gradient was observed across modalities (chromosomal microarray analysis [CMA], 16%; WES, 36%; WGS, 43%; p < 0.0001). Actionability estimates were robust across sensitivity analyses (54–64%). Genetic testing in NDDs functions not only as an etiological tool but as an input to personalised management, including pharmacological optimisation, comorbidity surveillance, and resolution of the diagnostic odyssey, albeit with very low certainty of evidence per Grading of Recommendations, Assessment, Development and Evaluations (GRADE), reflecting substantial heterogeneity and observational study design.
SN  - 1422-0067
ER  -