Bayat Allan, Borroto Maria Carla, Salian Smrithi, Zaki Maha S, Benkerroum Hind, Elbendary Hasnaa M, Nguyen Thi Tuyet Mai, Sadek Abdelrahim A, Carli Diana, Brusco Alfredo, Ferrero Giovanni Battista, Tartaglia Marco, Hay Eleanor, Krey Ilona, A Jamra Rami, Bartolomaeus Tobias, Knaus Alexej, Gleeson Joseph G, Houlden Henry, Dominik Natalia, Jackson Adam, Douzgou Houge Sofia, Banka Siddharth, Mohammadi-Asl Javad, Hajjari Mohammadreza, Azizimalamiri Reza, Nourbakhsh Pardis, Neissi Mostafa, Scardamaglia Annarita, Li Dianfan, Kinoshita Taroh, Maroofian Reza, Murakami Yoshiko, Campeau Philippe M
Department of Pediatrics, Danish Epilepsy Center, Dianalund, Denmark.
Department for Regional Health Research, University of Southern Denmark, Odense, Denmark.
Eur J Hum Genet. 2025 Sep 17. doi: 10.1038/s41431-025-01923-9.
PIGC encodes a protein essential for the biosynthesis of glycophosphatidylinositol-anchored proteins (GPI-APs). So far, three families with biallelic PIGC variants have been reported to exhibit developmental delay/intellectual disability and seizures. Our aim was to further elucidate the clinical and biomolecular characteristics of PIGC pathogenic or likely pathogenic variants. We established a cohort of 18 previously unreported probands. Clinical data were collected, and causative variants were identified though genome/exome sequencing. Variants were modelled in silico using AlphaFold2. Flow cytometry was performed to analyze the cell-surface expression of GPI-APs. The probands displayed a severe neurodevelopmental disorder characterized by developmental and cognitive impairment, early-onset and treatment-resistant seizures, and premature death affecting 10 out of 18 individuals (median age of 40 months, ranging from 40 days to 7 years). Additional features included brain imaging abnormalities (14/15), hypotonia (15/18), and skeletal anomalies (5/17). One patient exhibited mildly elevated alkaline phosphatase levels. All harbored biallelic PIGC variants, with 14 out of 18 of those being homozygous variants. Analysis of samples derived from probands and cellular models showed reduced cell surface levels of GPI-APs. This study confirms the association of PIGC biallelic variants with refractory seizures, severe developmental and cognitive impairments, and highlights their association with childhood-onset mortality. Additionally, it shows that dysfunctional PIGC results in defective biosynthesis of GPI-AP.
PIGC编码一种对于糖基磷脂酰肌醇锚定蛋白（GPI-APs）生物合成至关重要的蛋白质。到目前为止，已有三个携带双等位基因PIGC变异的家系被报道表现出发育迟缓/智力残疾和癫痫发作。我们的目的是进一步阐明PIGC致病或可能致病变异的临床和生物分子特征。我们建立了一个包含18名此前未报道的先证者的队列。收集了临床数据，并通过基因组/外显子组测序鉴定了致病变异。使用AlphaFold2对变异进行了计算机模拟。进行了流式细胞术分析以检测GPI-APs的细胞表面表达。这些先证者表现出一种严重的神经发育障碍，其特征为发育和认知障碍、早发性且难治性癫痫发作，以及过早死亡，18名个体中有10名受影响（中位年龄40个月，范围从40天至7岁）。其他特征包括脑成像异常（14/15）、肌张力减退（15/18）和骨骼异常（5/17）。一名患者碱性磷酸酶水平轻度升高。所有患者均携带双等位基因PIGC变异，其中18名中有14名是纯合变异。对来自先证者和细胞模型的样本分析显示GPI-APs的细胞表面水平降低。本研究证实了PIGC双等位基因变异与难治性癫痫、严重发育和认知障碍之间的关联，并突出了它们与儿童期发病死亡的关联。此外，研究表明功能失调的PIGC会导致GPI-AP生物合成缺陷。
