Clinical and Genetic Characterization of Inherited NPRL3 Splice Variants in Two Patients With Epilepsy

NPRL3-related epilepsy (NRE) is a GATORopathy characterized by focal seizures, with or without focal cortical dysplasia. Although NPRL3 variants have been associated with syndromes such as familial focal epilepsy with variable foci and sleep-related hypermotor epilepsy, the genotype-phenotype correlations in NRE remain poorly understood. This study aimed to investigate the clinical and genetic features of NRE in two Chinese families, together with a review of the genotype-phenotype spectrum.

Two pediatric Chinese patients with NRE were identified through whole-exome sequencing (WES). Clinical, neuroimaging, laboratory, and genetic data were analyzed. A review of reported NRE cases was conducted.

Inherited NPRL3 splice variants (NM_001077350.3: c.924 + 1G>A and c.925-1G>C) were identified in both probands using WES; both were inherited from their asymptomatic mothers. The patients presented with seizures starting at 1-2 years of age. Proband 1 experienced focal and focal to bilateral tonic-clonic seizures (FBTCS), while Proband 2 had focal seizures. Neuroimaging findings were normal. Patient 1 achieved seizure control with sodium valproate, oxcarbazepine, and lacosamide, while Patient 2 responded to oxcarbazepine and levetiracetam. A literature review of 41 articles identified 94 NPRL3 variants in 84 pedigrees and 23 cohort cases with epilepsy, revealing an estimated penetrance of 76% (162/214). Loss-of-function variants predominated (83%), while splice variants were relatively rare (13%). No clear genotype-phenotype correlations were observed, even in cases with identical NPRL3 variants.

The findings of the study highlight the genetic and clinical heterogeneity of NRE, which is characterized by incomplete penetrance and phenotypic variability. This underscores the importance of tailored antiepileptic management and the consideration of NPRL3 variants as causes of familial and sporadic epilepsy.