DLG3 variants caused X-linked epilepsy with/without neurodevelopmental disorders and the genotype-phenotype...

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• The DLG3 gene encodes a scaffold protein crucial for synaptic function.
• DLG3 variants are previously linked to X-linked intellectual developmental disorder-90.
• This study investigates the broader phenotypic impact of DLG3 gene variations.

Purpose of the Study:

• To explore the phenotypic spectrum associated with DLG3 gene variants.
• To investigate the genotype-phenotype correlation in individuals with DLG3-related disorders.
• To identify novel DLG3 variants in patients with unexplained epilepsy.

Main Methods:

• Whole-exome sequencing in trios of patients with unexplained epilepsy.
• Systematic review of previously reported DLG3 variants.
• In silico prediction of variant pathogenicity and analysis of protein-protein interactions.

Main Results:

• Seven unrelated epilepsy cases with novel DLG3 variants were identified.
• Variants were predicted to be damaging, affecting protein stability or interactions.
• A correlation was observed between variant location (functional domains vs. outside) and seizure control.
• Non-null variants showed a higher association with epilepsy compared to null variants.

Conclusions:

• DLG3 variants are associated with epilepsy, with or without neurodevelopmental disorder.
• The findings expand the known phenotypic spectrum of DLG3-related conditions.
• Genotype-phenotype correlations provide insights into the mechanisms of phenotypic variability in DLG3 disorders.