Diagnostic Yield and Clinical Utility of Chromosomal Microarray Analysis (CMA) in Children With Developmental Delay, Intellectual Disability, and Autism Spectrum Disorder: A Systematic Review.

Children with unexplained developmental delay (DD), intellectual disability (ID), and autism spectrum disorder (ASD) frequently undergo chromosomal microarray analysis (CMA). Two distinct questions arise: how often CMA identifies a causative variant, and whether that result changes clinical care. The purpose of this systematic review is to synthesize contemporary primary evidence on (i) the diagnostic yield of CMA in children with DD, ID, and/or ASD and the determinants of that yield, and (ii) the downstream clinical utility of a CMA result. Four electronic databases were searched from 1 January 2021 to 26 June 2026, with no language or country restriction. Eligible studies were original primary cohort or case-series analyses reporting patient-level diagnostic yield of postnatal CMA in pediatric DD/ID/ASD populations; non-original publication types were excluded. Methodological quality was appraised using a validated critical appraisal checklist for case series with pre-specified decision rules, and findings were synthesized narratively. Of 434 records identified, 13 studies met the eligibility criteria, comprising 11,535 children from nine countries. Study-level yield of pathogenic and likely pathogenic copy number variants ranged from 11.0% (95% CI 9.4-12.9) to 37.2% (95% CI 27.3-48.3); the median study-level yield was 18.5%, and 11 of 13 cohorts fell between 14% and 23%. Yield was lower in ASD (3.3-15.2%) than in DD/ID phenotypes (17.1-33.6%) and reached 27.4% where DD/ID co-occurred with multiple congenital anomalies. Variants of uncertain significance affected 2.7-12% of children. In the single cohort testing both modalities in the same patients, CMA yield exceeded karyotype yield (16.0% vs 7.0%). Seven studies were at low risk of bias, two at moderate risk of bias, and four at high risk of bias. No included study prospectively documented a change in clinical management. Study-level CMA yields were broadly consistent across diverse health systems, with a median of 18.5%. Yield is strongly phenotype-dependent, supporting pre-test phenotypic stratification rather than undifferentiated testing. Because no included cohort measured downstream management change, the clinical utility of CMA could not be quantified from contemporary evidence and remains a priority for prospective study.