Idiopathic focal epilepsy (IFE) is a group of self-limited epilepsies. The etiology for the majority of the patients with IFE remains elusive. We thus screened disease-causing variants in the patients with IFE.

Whole-exome sequencing was performed in a cohort of 323 patients with IFE. Protein modeling was performed to predict the effects of missense variants. The genotype–phenotype correlation of the newly defined causative gene was analyzed.

Four novel heterozygous variants in PGM3, including two de novo variants, were identified in four unrelated individuals with IFE. The variants included one truncating variant (c.1432C > T/p.Q478X) and three missense variants (c.478C > T/p.P160S, c.1239C > G/p.N413K, and c.1659T > A/p.N553K), which had no allele frequency in the gnomAD database. The missense variants were predicted to be damaging and affect hydrogen bonds with surrounding amino acids. Mutations Q478X, P160S, and N413K were associated with benign childhood epilepsy with centrotemporal electroencephalograph (EEG) spikes. P160S and N413K were located in the inner side of the enzyme active center. Mutation N553K was associated with benign occipital epilepsy with incomplete penetrance, located in the C-terminal of Domain 4. Further analysis demonstrated that previously reported biallelic PGM3 mutations were associated with severe immunodeficiency and/or congenital disorder of glycosylation, commonly accompanied by neurodevelopmental abnormalities, while monoallelic mutations were associated with milder symptoms like IFE.

The genetic and molecular evidence from the present study implies that the PGM3 variants identified in IFE patients lead to defects of the PGM3 gene, suggesting that the PGM3 gene is potentially associated with epilepsy. The genotype–phenotype relationship of PGM3 mutations suggested a quantitative correlation between genetic impairment and phenotypic severity, which helps explain the mild symptoms and incomplete penetrance in individuals with IFE.

特发性局灶性癫痫（IFE）是一组自限性癫痫。大多数 IFE 患者的病因仍然难以捉摸。因此，我们筛选了 IFE 患者的致病变异。

在 323 名 IFE 患者的队列中进行了全外显子组测序。进行蛋白质建模以预测错义变体的影响。分析了新定义的致病基因的基因型-表型相关性。

四种新的杂合变体PGM3，包括两个从头变异，在四个不相关的 IFE 个体中发现。变体包括一种截断变体（c.1432C > T/p.Q478X）和三个错义变体（c.478C > T/p.P160S、c.1239C > G/p.N413K 和 c.1659T > A/p .N553K)，在 gnomAD 数据库中没有等位基因频率。预计错义变体会破坏并影响与周围氨基酸的氢键。突变 Q478X、P160S 和 N413K 与伴有中央颞叶脑电图 (EEG) 尖峰的良性儿童癫痫相关。P160S和N413K位于酶活性中心的内侧。突变 N553K 与具有不完全外显率的良性枕部癫痫相关，位于结构域 4 的 C 末端。进一步分析表明，先前报道的双等位基因PGM3突变与严重的免疫缺陷和/或先天性糖基化障碍相关，通常伴有神经发育异常，而单等位基因突变与 IFE 等较轻的症状相关。

本研究的遗传和分子证据表明，PGM3在 IFE 患者中发现的变异导致PGM3基因，表明PGM3基因可能与癫痫有关。基因型-表型关系PGM3突变表明遗传损伤和表型严重程度之间存在定量相关性，这有助于解释 IFE 个体的轻度症状和不完全外显率。