CASK-related disorders are genetically defined neurodevelopmental syndromes. There is limited information about the effects of CASK mutations in human neurons. Therefore, we sought to delineate CASK-mutation consequences and neuronal effects using induced pluripotent stem cell-derived neurons from two mutation carriers. One male case with autism spectrum disorder carried a novel splice-site mutation and a female case with intellectual disability carried an intragenic tandem duplication. We show reduction of CASK protein in maturing neurons from the mutation carriers, which leads to significant downregulation of genes involved in presynaptic development and of CASK protein interactors. Furthermore, CASK-deficient neurons showed decreased inhibitory presynapse size as indicated by VGAT staining, which may alter the excitatory–inhibitory (E/I) balance in developing neural circuitries. Using in vivo magnetic resonance spectroscopy quantification of GABA in the male mutation carrier, we further highlight the possibility to validate in vitro cellular data in the brain. Our data show that future pharmacological and clinical studies on targeting presynapses and E/I imbalance could lead to specific treatments for CASK-related disorders.

CASK相关疾病是遗传定义的神经发育综合征。关于CASK突变对人类神经元的影响的信息有限。因此，我们试图使用来自两个突变携带者的诱导多能干细胞衍生神经元来描述CASK突变后果和神经元效应。一名患有自闭症谱系障碍的男性病例携带新的剪接位点突变，一名患有智力障碍的女性病例携带基因内串联重复。我们显示来自突变携带者的成熟神经元中 CASK 蛋白的减少，这导致参与突触前发育的基因和 CASK 蛋白相互作用物的显着下调。此外，木桶- 有缺陷的神经元显示出抑制性突触前大小减小，如 VGAT 染色所示，这可能会改变发育中的神经回路中的兴奋 - 抑制 (E/I) 平衡。使用体内磁共振波谱量化雄性突变携带者中的 GABA，我们进一步强调了验证大脑中体外细胞数据的可能性。我们的数据表明，未来针对突触前和 E/I 失衡的药理学和临床研究可能会导致针对CASK相关疾病的特定治疗。