Cohen syndrome (CS) is a rare multisystem autosomal recessive disorder associated with mutations in VPS13B (vacuolar protein sorting homolog 13B). The NAPB-related neurodevelopmental disorder is characterized mainly by early-onset epileptic encephalopathy (EOEE) and is associated with mutations in NAPB that encodes for SNAP-beta (soluble NSF attachment protein beta). Here we describe male triplets, clinically presenting with the phenotype of subtle but distinctive facial features, intellectual disability, increased body weight, neonatal EOEE, and prominently variable abnormal behaviors of autism and sexual arousal. The EEG showed multifocal epilepsy, while the brain MRI showed no abnormalities. Diagnostic exome sequencing (ES), the applied next-generation sequencing approach, revealed the interesting finding of two novel homozygous variants in two genes: VPS13B missense variant (c.8516G > A) and NAPB splice-site loss (c.354 + 2 T > G). Sanger sequencing verified the segregation of the two recessive gene variants with the phenotype in family members. The prediction algorithms support the pathogenicity of these variants. Homozygosity mapping of ES data of this consanguineous family revealed multiple chromosomal regions of homozygosity stretches with the residing of VPS13B (chr8: 100830758G > A) and NAPB (Chr20: 23,375,774 A > C) variants within the largest homozygous blocks further supporting the disease-genes causal role. Interestingly, the functions of the two proteins; VPS13B, a transmembrane protein involved in intracellular protein transport, and SNAP-beta involved in neurotransmitters release at the neuronal synaptic complexes, have been associated with Golgi-mediated vesicular trafficking. Our ES findings provide new insights into the pathologic mechanism underlying the expansion of the neurodevelopmental spectrum in CS and further highlight the importance of Golgi and Golgi-membrane-related proteins in the development of neurodevelopmental syndromes associated with early-onset non-channelopathy epilepsy. To our knowledge, this is the first report documenting multifocal EOEE in CS patients with the association of a pathogenic NAPB variant.

Cohen 综合征 (CS) 是一种罕见的多系统常染色体隐性遗传病，与VPS13B（液泡蛋白分选同系物 13B）突变相关。NAPB相关神经发育障碍的主要特征是早发性癫痫性脑病 (EOEE)，并且与NAPB突变有关编码 SNAP-beta（可溶性 NSF 附着蛋白 beta）。在这里，我们描述了男性三胞胎，临床表现出微妙但独特的面部特征、智力障碍、体重增加、新生儿 EOEE 以及自闭症和性唤起的显着变异异常行为的表型。脑电图显示多灶性癫痫，而脑部 MRI 未见异常。诊断外显子组测序 (ES)，即应用的下一代测序方法，揭示了两个基因中两个新的纯合变异的有趣发现：VPS13B错义变异 (c.8516G > A) 和NAPB剪接位点丢失 (c.354 + 2 T > G)。Sanger测序验证了两个隐性基因变异与家族成员表型的分离。预测算法支持这些变异的致病性。该近亲家族 ES 数据的纯合子作图揭示了VPS13B (chr8: 100830758G > A) 和NAPB驻留的多个纯合子染色体区域(Chr20: 23,375,774 A > C) 最大纯合块内的变异进一步支持了疾病基因的因果作用。有趣的是，这两种蛋白质的功能；VPS13B（一种参与细胞内蛋白质转运的跨膜蛋白）和参与神经元突触复合体神经递质释放的 SNAP-beta 与高尔基体介导的囊泡运输有关。我们的 ES 发现为 CS 中神经发育谱扩展的病理机制提供了新的见解，并进一步强调了高尔基体和高尔基体膜相关蛋白在与早发性非通道病癫痫相关的神经发育综合征发展中的重要性。据我们所知，这是第一份记录 CS 患者多灶性 EOEE 与病原体相关的报告NAPB变体。