JAMA Netw Open. 2025 Mar 3;8(3):e251807. doi: 10.1001/jamanetworkopen.2025.1807.
ABSTRACT
IMPORTANCE: Copy number variants (CNVs) and single-nucleotide variations (SNVs) or insertions and deletions are key genetic contributors to neurodevelopmental disorders (NDDs). Traditionally, chromosome microarray and exome sequencing (ES) have been used to detect CNVs and single gene variants, respectively.
OBJECTIVE: To identify genetic variants causing NDDs and evaluate the diagnostic yield and clinical utility of ES by simultaneously analyzing CNVs and SNVs in patients with NDDs and their biologic parents (trios).
DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study included pediatric patients with suspected NDDs who visited Shanghai Children’s Hospital between January 1, 2018, and December 31, 2023. ES was used to investigate trios (trio-ES) including patients with NDDs who remained undiagnosed after phenotype identification and underwent gene panel testing, multiplex ligation-dependent probe amplification, or karyotyping. Comprehensive clinical and laboratory data were collected. Data were analyzed from July 2022 to December 2023.
EXPOSURE: NDDs, characterized by global developmental delay or intellectual disability.
MAIN OUTCOMES AND MEASURES: The study measured the overall diagnostic yield of SNVs and CNVs in the NDD cohort as well as within NDD syndromic subtypes.
RESULTS: Of the 1106 patients with NDDs, 731 (66.1%) were male. The mean (SD) age of patients at diagnosis was 3.80 (2.82) years. The overall diagnostic yield of trio-ES was 46.1% (510 diagnoses among 1106 patients), with 149 CNVs (13.5%), 355 SNVs (32.1%), and 4 cases of uniparental disomy (0.4%). Codiagnosis of SNVs and CNVs occurred in 2 cases (0.2%). Among the trios, 812 candidate germline variants were identified, including 634 SNVs (78.1%), 174 CNVs (21.4%), and 4 cases of uniparental disomy (0.5%). Of these, 423 SNVs (66.7%) and 157 CNVs (90.2%) were diagnostic variants, while 211 SNVs (33.3%) and 17 CNVs (9.8%) were variants of uncertain significance. Sixteen CNVs smaller than 20 kilobase were detected using ES.
CONCLUSIONS AND RELEVANCE: In this cohort study, trio-ES, by simultaneously detecting SNVs and CNVs, achieved a diagnostic yield of 46.1%. Trio-ES may be particularly applicable for identifying small CNVs and recessive genetic diseases involving both SNVs and CNVs. These findings suggest that in clinical practice, simultaneously analyzing SNVs and CNVs using trio-ES data has a favorable genetic diagnostic yield for children with NDDs.
PMID:40131272 | DOI:10.1001/jamanetworkopen.2025.1807
