Glycosylphosphatidylinositol (GPI)-anchored proteins are critical for embryogenesis, neurogenesis, and cell signaling. Variants in several genes participating in GPI biosynthesis and processing lead to decreased cell surface presence of GPI-anchored proteins (GPI-APs) and cause inherited GPI deficiency disorders (IGDs). In this report, we describe 12 individuals from nine unrelated families with 10 different bi-allelic PIGK variants. PIGK encodes a component of the GPI transamidase complex, which attaches the GPI anchor to proteins. Clinical features found in most individuals include global developmental delay and/or intellectual disability, hypotonia, cerebellar ataxia, cerebellar atrophy, and facial dysmorphisms. The majority of the individuals have epilepsy. Two individuals have slightly decreased levels of serum alkaline phosphatase, while eight do not. Flow cytometric analysis of blood and fibroblasts from affected individuals showed decreased cell surface presence of GPI-APs. The overexpression of wild-type (WT) PIGK in fibroblasts rescued the levels of cell surface GPI-APs. In a knockout cell line, transfection with WT PIGK also rescued the GPI-AP levels, but transfection with the two tested mutant variants did not. Our study not only expands the clinical and known genetic spectrum of IGDs, but it also expands the genetic differential diagnosis for cerebellar atrophy. Given the fact that cerebellar atrophy is seen in other IGDs, flow cytometry for GPI-APs should be considered in the work-ups of individuals presenting this feature.

中文翻译：

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GPI转酰胺酶亚基PIGK中的双等位基因变异会导致神经发育综合征，并伴有低钾症，小脑萎缩和癫痫。

糖基磷脂酰肌醇（GPI）锚定的蛋白对于胚胎发生，神经发生和细胞信号传导至关重要。参与GPI生物合成和加工的几个基因的变异导致GPI锚定蛋白（GPI-AP）的细胞表面存在减少，并导致遗传性GPI缺乏症（IGD）。在本报告中，我们描述了来自9个无关家庭的12个人，具有10个不同的双等位基因PIGK变体。PIGK编码GPI转酰胺酶复合物的一个成分，该成分将GPI锚连接到蛋白质上。在大多数个体中发现的临床特征包括整体发育迟缓和/或智力障碍，肌张力低下，小脑性共济失调，小脑萎缩和面部畸形。大多数人患有癫痫病。两个人的血清碱性磷酸酶水平略有下降，而八个没有。来自受影响个体的血液和成纤维细胞的流式细胞仪分析表明，GPI-AP的细胞表面存在减少。成纤维细胞中野生型（WT）PIGK的过表达挽救了细胞表面GPI-AP的水平。在敲除细胞系中，WT PIGK的转染也挽救了GPI-AP的水平，但两个测试突变体的转染却没有。我们的研究不仅扩大了IGD的临床和已知的遗传谱，而且还扩大了小脑萎缩的遗传鉴别诊断。鉴于在其他IGD中可见小脑萎缩的事实，应在表现出该特征的个体的检查中考虑GPI-AP的流式细胞仪。成纤维细胞中野生型（WT）PIGK的过表达挽救了细胞表面GPI-AP的水平。在敲除细胞系中，WT PIGK的转染也挽救了GPI-AP的水平，但两个测试突变体的转染却没有。我们的研究不仅扩大了IGD的临床和已知的遗传谱，而且还扩大了小脑萎缩的遗传鉴别诊断。鉴于在其他IGD中可见小脑萎缩的事实，应在表现出该特征的个体的检查中考虑GPI-AP的流式细胞术。成纤维细胞中野生型（WT）PIGK的过表达挽救了细胞表面GPI-AP的水平。在敲除细胞系中，WT PIGK的转染也挽救了GPI-AP的水平，但两个测试突变体的转染却没有。我们的研究不仅扩大了IGD的临床和已知的遗传谱，而且还扩大了小脑萎缩的遗传鉴别诊断。鉴于在其他IGD中可见小脑萎缩的事实，应在表现出该特征的个体的检查中考虑GPI-AP的流式细胞仪。我们的研究不仅扩大了IGD的临床和已知的遗传谱，而且还扩大了小脑萎缩的遗传鉴别诊断。鉴于在其他IGD中可见小脑萎缩的事实，应在表现出该特征的个体的检查中考虑GPI-AP的流式细胞术。我们的研究不仅扩大了IGD的临床和已知的遗传谱，而且还扩大了小脑萎缩的遗传鉴别诊断。鉴于在其他IGD中可见小脑萎缩的事实，应在表现出该特征的个体的检查中考虑GPI-AP的流式细胞术。