Heterozygous RELN missense variants associated with genetic generalized epilepsy

Area of Science:

• Neurogenetics
• Epilepsy Research

Background:

• The RELN gene encodes Reelin, a crucial secreted glycoprotein for brain development and function.
• Genetic factors play a significant role in the etiology of epilepsy.

Purpose of the Study:

• To investigate the association between the RELN gene and genetic generalized epilepsy (GGE).
• To identify novel RELN variants in patients with GGE and characterize their clinical and molecular features.

Main Methods:

• Whole-exome sequencing was performed on 92 GGE patients.
• RELN variants were identified using computational modeling and functional assays.
• Reelin secretion and transport were analyzed in cell-based assays.

Main Results:

• Three novel pathogenic RELN variants (c.2260C>T/p.R754W, c.2914C>G/p.P972A, c.3029G>A/p.R1010H) were identified in 3.26% of patients.
• Patients with these variants presented with adolescence-onset generalized seizures, mild cognitive impairment, and good response to medication.
• Mutant Reelin variants impaired protein secretion and transport in cellular models, suggesting a loss-of-function mechanism.

Conclusions:

• The RELN gene is potentially associated with GGE.
• RELN variants are linked to a relatively mild GGE phenotype.
• The pathogenic mechanism likely involves impaired Reelin secretion and transport, indicating a loss-of-function effect.