Molecular Diagnosis and Pathway Convergence in Neurodevelopmental Disorders: An Integrative Genomic Study of 1,011 Patients

Background Genetic factors are critical to diagnosing neurodevelopmental disorders (NDDs). Despite advances in genetic diagnostics, a considerable proportion of patients remain undiagnosed, highlighting the urgent need to identify underlying genetic etiologies and discover additional pathogenic genes and molecular mechanisms. Method Whole-exome sequencing (WES), trio-WES, panel sequencing, chromosomal microarray analysis (CMA), or multiplex ligation-dependent probe amplification (MLPA) were used for identifying potential variant. Comprehensive clinical and laboratory data were collected. All patients were classified into 18 phenotypic subgroups. GWAS was conducted for sequencing-negative cases. Results Of the 1011 patients with GDD/ID, the most comorbid symptoms were abnormal MRI findings, craniofacial malformations, and malnutrition/feeding difficulties/growth retardation. The overall diagnostic rate was 54% (508/940), with 343(36.5%) single-nucleotide variations (SNVs) and 157(16.7%) Copy number variants (CNVs). Among SNV-positive cases, we identified 166/430(38.6% ) novel variants and 179/430 (41.6%) de novo variants. In CNV-positive cases, the top recurrent cytobands were 15q11.2-q13.1, Xq28, and 7q11.2. GWAS analysis showed that genetically negative cases were significant enrichment in the Rap1 signaling and O-glycosylation modification, while positive cases significantly enriched in axonogenesis and chromatin remodeling. Integrated analysis of two sets highlighted convergence on O-glycosylation and calcium response. Protein-protein interaction analysis of 47 overlapping genes identified the RAS-MAPK signaling pathway. Conclusion: Our findings further supported the clinical value of trio-WES/WES as a first-tier diagnostic strategy for NDDs. Importantly, O-glycosylation modification emerges as a critical molecular mechanism in NDDs, offering a potential convergence may reveal common neurobiological processes.