Germline functional variants contribute to neurodevelopmental trajectories in children with autism spectrum disorder or intellectual disability.

While genetic studies have identified risk variants for autism spectrum disorder (ASD) and intellectual disability (ID), their role in informing neurodevelopmental outcomes remains unclear. This study aimed to investigate the association between functional germline variants (FGVs) and neurodevelopmental trajectories in children with ASD or ID. The study cohort comprised 484 children (448 with ASD or ID and 36 controls) recruited at Asan Medical Center between 2018 and 2023. Diagnoses and clinical variables were assessed at baseline and the index age (60-72 months). Whole exome sequencing was conducted, and FGVs were defined based on public databases and functional impact. Pathway analysis was performed to identify biological pathways associated with ASD or ID for these FGVs. Children with ASD or ID showed a significantly higher burden of FGVs in ASD/NDD-related genes compared to controls (P = 0.012). Among children with ASD or ID, mutations were enriched in lysine degradation and dopaminergic synapse pathways. The lysine degradation pathway showed a weak but significant correlation with increased severity of ASD symptoms (Childhood Autism Rating Scale, rho = 0.097, P = 0.0499) and poorer adaptive functioning (Vineland Adaptive Behavior Scale Adaptive Behavior Composite Score, rho = -0.12, P = 0.023). Mutations in this pathway were independently associated with gaining diagnoses of ASD or ID (OR = 4.25, P = 0.017), specifically earlier diagnosis of a new ASD or ID at the index age (HR = 3.64, P = 0.02). In conclusion, our findings suggest that FGVs, particularly those in the lysine degradation pathway, may play a critical role in the neurodevelopmental trajectories of children with ASD or ID.