Potential role of SLC6A3 in neurodevelopmental impairments associated with corpus callosum abnormalities: insights from CNV analysis and clinical phenotyping.

Objective: This study aimed to investigate the role of pathogenic copy number variations (CNVs) in neurodevelopmental impairments among children with corpus callosum abnormalities (CCAs). We focused primarily on SLC6A3 associated mechanisms and aimed to delineate genotype-phenotype correlations in our cases.

Methods: From January 2021 to July 2023, 13 children with MRI-confirmed CCAs underwent chromosomal microarray analysis (CMA) for CNV detection. We performed bioinformatic analyses (Gene Ontology, STRING network) to identify neurodevelopmental genes within pathogenic CNVs, and clinical follow up assessed neurobehavioral outcomes.

Results: We identified pathogenic CNVs in 3/13 cases (23.08%). Specifically, Case 8 harbored a 43.05-Mb duplication (5p15.33p12) encompassing SLC6A3, a dopamine transporter gene linked to synaptic signaling. Interaction network analysis suggested that SLC6A3 was the most interconnected gene, providing evidence of its role in CCAs. Clinically, 84.6% of cases (11/13) exhibited psychomotor delay, while 15.4% of cases (2/13) developed seizure. Notably, we observed hearing impairment and psychomotor developmental delay in Case 8 with a SLC6A3 duplication, further suggesting dopaminergic dysregulation in callosal connectivity.

Conclusion: Our study suggests that SLC6A3 may represent a potential contributor to neurodevelopmental impairments in CCAs. Further, CMA-based CNV screening is critical for early intervention in high-risk children. These findings bridge genetic etiology with clinical phenotypes and offer insights into future targeted therapeutic strategies.