Genetic testing and analysis of 1024 children with global developmental delay or intellectual disability: a single-center cohort study

Global developmental delay (GDD) and intellectual disability (ID) are common neurodevelopmental disorders with a strong genetic basis. However, comprehensive large-cohort analyses integrating genotype-phenotype correlations and functional mechanisms remain limited. This study aimed to systematically characterize the clinical and genetic spectrum of GDD/ID in a large single-center cohort and to explore the functional attributes of disease-causing genes. We retrospectively analyzed 1024 children diagnosed with GDD or ID who underwent genetic testing, including trio whole-exome sequencing (trio-WES), proband-only WES, and clinical exome sequencing. Clinical phenotypes were categorized, and functional enrichment analyses were conducted for genes associated with diagnostic and probable diagnostic results. A genetic diagnosis was achieved in 48.1% of patients, with trio-WES demonstrating a significantly higher diagnostic yield than proband-only approaches. Pathogenic variants mainly comprised single-nucleotide variants and copy number variants. Identified genes were predominantly involved in protein homeostasis, synaptic and ion channel function, epigenetic regulation, and key developmental signaling pathways. Distinct genotype-phenotype associations were observed among clinical subgroups, including enrichment of synaptic-related genes in epilepsy-associated GDD/ID and epigenetic regulatory genes in patients with facial dysmorphism. CONCLUSION: This study provides a comprehensive characterization of the genetic landscape of GDD/ID in a large single-center cohort and identifies distinct genotype-phenotype correlations and convergent molecular pathways underlying these disorders. WHAT IS KNOWN: • Global developmental delay (GDD) and intellectual disability (ID) are highly heterogeneous neurodevelopmental disorders with a strong genetic basis. WHAT IS NEW: • We report a large single-center cohort of 1024 children with GDD/ID, providing a comprehensive overview of the genetic landscape and diagnostic yield of different sequencing strategies. • Our study systematically integrates genotype-phenotype correlations with functional pathway analyses, highlighting key molecular mechanisms underlying GDD/ID and supporting refined molecular stratification.