To explore the phenotype spectrum of DEPDC5 variants and the possible mechanisms underlying phenotypical variation, we performed targeted next-generation sequencing in 305 patients with focal epilepsies and 91 patients with generalized epilepsies. Protein modeling was performed to predict the effects of missense mutations. All previously reported epilepsy-related DEPDC5 variants were reviewed. The genotype–phenotype correlations with molecular sub-regional implications were analyzed. We identified a homozygous DEPDC5 mutation (p.Pro1031His) in a case with focal cortical dysplasia and eight heterozygous mutations in 11 families with mild focal epilepsies, including 13 patients in eight families with focal epilepsy with febrile seizures plus/febrile seizures (FEFS + /FS). The mutations included one termination codon mutation (p.Ser1601_Ter1604del_ext133), three truncating mutations (p.Val151Serfs∗27, p.Arg239∗, and p.Arg838∗), and four missense mutations (p.Tyr7Cys, p.Tyr836Cys, p.Pro1031His, and p.Gly1545Ser) that were predicted to affect hydrogen bonds and protein stability. Analysis on epilepsy-related DEPDC5 variants revealed that malformations of cortical development (MCDs) had a tendency of higher frequency of null mutations than those without MCD. MCD-associated heterozygous missense mutations were clustered in structural axis for binding arrangement (SABA) domain and close to the binding sites to NPRL2/NPRL3 complex, whereas those associated with FEFS + /FS were a distance away from the binding sites. Evidence from four aspects and one possible evidence from sub-regional implication suggested MCD and FEFS + /FS as phenotypes of DEPDC5 variants. This study suggested that the phenotypes of DEPDC5 variants vary from mild FEFS + /FS to severe MCD. Heterozygous DEPDC5 mutations are generally less pathogenic and commonly associated with mild phenotypes. Bi-allelic mutations and second hit of somatic mutations, together with the genotype–phenotype correlation and sub-regional implication of DEPDC5 variants, explain severe phenotypes.

中文翻译：

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DEPDC5 变体与皮质发育畸形和局灶性癫痫伴发热性癫痫发作加/发热性癫痫发作相关：分子亚区域效应的作用

为了探索 DEPDC5 变异的表型谱和表型变异的可能机制，我们对 305 名局灶性癫痫患者和 91 名全身性癫痫患者进行了靶向下一代测序。进行蛋白质建模以预测错义突变的影响。审查了所有先前报告的癫痫相关 DEPDC5 变体。分析了基因型-表型与分子亚区域影响的相关性。我们在一个局灶性皮质发育不良的病例中发现了纯合 DEPDC5 突变（p.Pro1031His），在 11 个轻度局灶性癫痫家族中发现了 8 个杂合突变，其中包括 8 个局灶性癫痫家族中的 13 名患者伴有热性惊厥加 / 热性惊厥 (FEFS + / FS）。突变包括一个终止密码子突变 (p. Ser1601_Ter1604del_ext133)、三个截断突变（p.Val151Serfs∗27、p.Arg239∗ 和 p.Arg838∗）和四个错义突变（p.Tyr7Cys、p.Tyr836Cys、p.Pro1031His15His）影响氢键和蛋白质稳定性。对癫痫相关 DEPDC5 变体的分析表明，与没有 MCD 的人相比，皮质发育畸形 (MCD) 的无效突变频率更高。MCD 相关的杂合错义突变聚集在结合排列（SABA）结构域的结构轴上，靠近与 NPRL2/NPRL3 复合物的结合位点，而与 FEFS + /FS 相关的那些与结合位点相距一段距离。来自四个方面的证据和来自亚区域暗示的一个可能的证据表明 MCD 和 FEFS + /FS 作为 DEPDC5 变体的表型。该研究表明 DEPDC5 变体的表型从轻度 FEFS + /FS 到严重 MCD 不等。杂合 DEPDC5 突变通常致病性较低，通常与轻度表型相关。双等位基因突变和体细胞突变的第二次命中，以及 DEPDC5 变异的基因型-表型相关性和亚区域影响，解释了严重的表型。