Abstract：
BACKGROUND: NPRL2-related epilepsy, caused by pathogenic germline variants of the NPRL2 gene, is a newly discovered childhood epilepsy linked to enhanced mTORC1 signalling. However, the phenotype and genotype of NPRL2 variants are still poorly understood. Here, we summarize the association between the phenotype and genotype of NPRL2-related epilepsy.
METHODS: A retrospective analysis was conducted for four Chinese children with epilepsy due to likely pathogenic NPRL2 variants identified through whole-exome sequencing (WES). Previous reports of patients with NPRL2-related epilepsy were reviewed systematically.
RESULTS: One of our patients presented focal epilepsy involving the central region, which should be distinguished from self-limited epilepsy with centrotemporal spikes (SeLECTS). The four novel likely pathogenic NPRL2 variants consisted of two nonsense variants, one frameshift variant, and one copy number variant (CNV). Bioinformatics analysis revealed the two nonsense variants to be highly conserved and cause alterations in protein structure. Including our four cases, a total of 33 patients with NPRL2-related epilepsy have been identified to date. The most common presentation is focal epilepsy (70%), including sleep-related hypermotor epilepsy (SHE), temporal lobe epilepsy (TLE), and frontal lobe epilepsy (FLE). Infantile epileptic spasms syndrome (IESS) is also a notable feature of NPRL2-related epilepsy. Malformations of cortical development (MCD, 8/20), especially focal cortical dysplasia (FCD, 6/20), are common neuroimaging abnormalities. Two-thirds of the NPRL2 variants reported are loss of function (LoF) (14/21). Among these mutations, c.100C>T (p.Arg34*) and c.314T>C (p.Leu105Pro) have been detected in two families (likely due to a founder effect).
CONCLUSIONS: NPRL2-related epilepsy shows high phenotypic and genotypic heterogeneity. Our study expands the genotype spectrum of NPRL2-related epilepsy, and the phenotype of focal epilepsy involving the central region should be clearly distinguished with SeLECTS, with reference value for clinical diagnosis.
METHODS: A retrospective analysis was conducted for four Chinese children with epilepsy due to likely pathogenic NPRL2 variants identified through whole-exome sequencing (WES). Previous reports of patients with NPRL2-related epilepsy were reviewed systematically.
RESULTS: One of our patients presented focal epilepsy involving the central region, which should be distinguished from self-limited epilepsy with centrotemporal spikes (SeLECTS). The four novel likely pathogenic NPRL2 variants consisted of two nonsense variants, one frameshift variant, and one copy number variant (CNV). Bioinformatics analysis revealed the two nonsense variants to be highly conserved and cause alterations in protein structure. Including our four cases, a total of 33 patients with NPRL2-related epilepsy have been identified to date. The most common presentation is focal epilepsy (70%), including sleep-related hypermotor epilepsy (SHE), temporal lobe epilepsy (TLE), and frontal lobe epilepsy (FLE). Infantile epileptic spasms syndrome (IESS) is also a notable feature of NPRL2-related epilepsy. Malformations of cortical development (MCD, 8/20), especially focal cortical dysplasia (FCD, 6/20), are common neuroimaging abnormalities. Two-thirds of the NPRL2 variants reported are loss of function (LoF) (14/21). Among these mutations, c.100C>T (p.Arg34*) and c.314T>C (p.Leu105Pro) have been detected in two families (likely due to a founder effect).
CONCLUSIONS: NPRL2-related epilepsy shows high phenotypic and genotypic heterogeneity. Our study expands the genotype spectrum of NPRL2-related epilepsy, and the phenotype of focal epilepsy involving the central region should be clearly distinguished with SeLECTS, with reference value for clinical diagnosis.
摘要：
背景：NPRL2相关癫痫，由NPRL2基因的致病性种系变异引起，是一种新发现的儿童癫痫，与mTORC1信号增强有关。然而,NPRL2变体的表型和基因型仍然知之甚少.这里,我们总结了NPRL2相关癫痫的表型和基因型之间的关联.
方法：对4例中国儿童癫痫患者进行回顾性分析，原因是通过全外显子组测序（WES）鉴定出可能的致病性NPRL2变异。系统回顾了以前关于NPRL2相关癫痫患者的报道。
结果：我们的一位患者出现局灶性癫痫，累及中央区，应与具有中央颞部尖峰的自限性癫痫（SeLECTS）区分开。四个新的可能致病性NPRL2变体由两个无义变体组成，一个移码变体，和一个拷贝数变体(CNV)。生物信息学分析显示，这两种无义变体高度保守，并导致蛋白质结构发生变化。包括我们的四个案例，迄今为止,共发现33例NPRL2相关癫痫患者.最常见的表现是局灶性癫痫（70％），包括睡眠相关的运动过度癫痫（SHE），颞叶癫痫（TLE），额叶癫痫（FLE）。婴儿癫痫性痉挛综合征（IESS）也是NPRL2相关癫痫的显着特征。皮质发育畸形（MCD，8/20），尤其是局灶性皮质发育不良（FCD，6/20),是常见的神经影像学异常。报告的NPRL2变体的三分之二是功能丧失(LoF)(14/21)。在这些突变中,c.100C>T（p。Arg34*）和c.314T>C（p。Leu105Pro）已在两个家庭中被检测到（可能是由于创始人的影响）。
结论：NPRL2相关癫痫表现出高度的表型和基因型异质性。我们的研究扩展了NPRL2相关癫痫的基因型谱，涉及中央区的局灶性癫痫的表型应与SeLECTS明确区分，对临床诊断具有参考价值。
方法：对4例中国儿童癫痫患者进行回顾性分析，原因是通过全外显子组测序（WES）鉴定出可能的致病性NPRL2变异。系统回顾了以前关于NPRL2相关癫痫患者的报道。
结果：我们的一位患者出现局灶性癫痫，累及中央区，应与具有中央颞部尖峰的自限性癫痫（SeLECTS）区分开。四个新的可能致病性NPRL2变体由两个无义变体组成，一个移码变体，和一个拷贝数变体(CNV)。生物信息学分析显示，这两种无义变体高度保守，并导致蛋白质结构发生变化。包括我们的四个案例，迄今为止,共发现33例NPRL2相关癫痫患者.最常见的表现是局灶性癫痫（70％），包括睡眠相关的运动过度癫痫（SHE），颞叶癫痫（TLE），额叶癫痫（FLE）。婴儿癫痫性痉挛综合征（IESS）也是NPRL2相关癫痫的显着特征。皮质发育畸形（MCD，8/20），尤其是局灶性皮质发育不良（FCD，6/20),是常见的神经影像学异常。报告的NPRL2变体的三分之二是功能丧失(LoF)(14/21)。在这些突变中,c.100C>T（p。Arg34*）和c.314T>C（p。Leu105Pro）已在两个家庭中被检测到（可能是由于创始人的影响）。
结论：NPRL2相关癫痫表现出高度的表型和基因型异质性。我们的研究扩展了NPRL2相关癫痫的基因型谱，涉及中央区的局灶性癫痫的表型应与SeLECTS明确区分，对临床诊断具有参考价值。
