Evaluation of Diagnostic Yield and Clinical Utility of Trio Whole‐Genome Sequencing in Children With GDD / IDD in China

Accurate diagnosis and timely intervention are essential for improving outcomes in children with global developmental delay (GDD) or intellectual developmental disorder (IDD). Although genomic sequencing has improved diagnostic yield, studies integrating long-term clinical follow-up remain limited, hindering clinical translation. In this cohort study, 122 Chinese children with GDD/IDD were enrolled from a single center (2018-2023) and underwent Trio whole-genome sequencing (Trio-WGS). Trio-WGS achieved a 39.3% (48/122) diagnostic yield, identifying pathogenic/likely pathogenic variants in 48 cases, including 35 SNVs/Indels and 13 CNVs. De novo variants accounted for 75% (36/48) of findings, with autosomal dominant inheritance predominant. Enrichment analysis revealed that, beyond the generic neurodevelopmental signature, the GDD/IDD diagnostic gene set was specifically enriched for presynaptic function, GABAergic/chloride transport, and chromatin remodeling. A multidisciplinary team used results to optimize care: 3 children improved with targeted therapy, 30 had comorbidity management adjusted, 17 received diet modifications, and 7 families pursued preimplantation genetic testing. This study holds great significance for improving the genetic diagnosis rate of GDD/IDD and identifying new mutations, while also providing valuable information for the treatment of GDD/IDD and reproductive guidance.