Heterozygous PGM3 Variants Are Associated With Idiopathic Focal Epilepsy With Incomplete Penetrance

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Idiopathic focal epilepsy (IFE) is a group of self-limited epilepsies with largely unknown causes.
• Screening for disease-causing variants is crucial for understanding IFE etiology.

Purpose of the Study:

• To screen for disease-causing variants in patients with idiopathic focal epilepsy (IFE).
• To investigate the genotype-phenotype correlation of newly identified causative genes.

Main Methods:

• Whole-exome sequencing in 323 IFE patients.
• Protein modeling to predict missense variant effects.
• Genotype-phenotype correlation analysis.

Main Results:

• Four novel heterozygous PGM3 variants (1 truncating, 3 missense) identified in four unrelated IFE patients.
• Missense variants predicted as damaging, affecting protein structure and function.
• PGM3 variants associated with specific epilepsy syndromes (benign childhood epilepsy, benign occipital epilepsy) with varying penetrance.
• Monoallelic PGM3 mutations linked to milder IFE phenotypes compared to severe phenotypes seen with biallelic mutations.

Conclusions:

• PGM3 variants identified in IFE patients suggest PGM3 is a potential causative gene for epilepsy.
• Genotype-phenotype correlation indicates a quantitative relationship between genetic defect severity and epilepsy symptom severity.
• This finding helps explain the milder symptoms and incomplete penetrance observed in some IFE individuals.