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

BACKGROUND

The gene encodes disks large membrane-associated guanylate kinase scaffold protein 3, which plays essential roles in the clustering of N-methyl-D-aspartate receptors (NMDARs) at excitatory synapses. Previously, has been identified as the causative gene of X-linked intellectual developmental disorder-90 (XLID-90; OMIM# 300850). This study aims to explore the phenotypic spectrum of and the genotype-phenotype correlation.

METHODS

Trios-based whole-exome sequencing was performed in patients with epilepsy of unknown causes. To analyze the genotype-phenotype correlations, previously reported variants were systematically reviewed.

RESULTS

variants were identified in seven unrelated cases with epilepsy. These variants had no hemizygous frequencies in controls. All variants were predicted to be damaging by silico tools and alter the hydrogen bonds with surrounding residues and/or protein stability. Four cases mainly presented with generalized seizures, including generalized tonic-clonic and myoclonic seizures, and the other three cases exhibited secondary generalized tonic-clonic seizures and focal seizures. Multifocal discharges were recorded in all cases during electroencephalography monitoring, including the four cases with generalized discharges initially but multifocal discharges after drug treating. Protein-protein interaction network analysis revealed that interacts with 52 genes with high confidence, in which the majority of disease-causing genes were associated with a wide spectrum of neurodevelopmental disorder (NDD) and epilepsy. Three patients with variants locating outside functional domains all achieved seizure-free, while the four patients with variants locating in functional domains presented poor control of seizures. Analysis of previously reported cases revealed that patients with non-null variants presented higher percentages of epilepsy than those with null variants, suggesting a genotype-phenotype correlation.

SIGNIFICANCE

This study suggested that variants were associated with epilepsy with/without NDD, expanding the phenotypic spectrum of . The observed genotype-phenotype correlation potentially contributes to the understanding of the underlying mechanisms driving phenotypic variation.