We investigated seven children from six families to expand the phenotypic spectrum associated with an early infantile epileptic encephalopathy caused by biallelic pathogenic variants in the phosphatidylinositol glycan anchor biosynthesis class Q (PIGQ) gene. The affected children were all identified by clinical or research exome sequencing. Clinical data, including EEGs and MRIs, was comprehensively reviewed and flow cytometry and transfection experiments were performed to investigate PIGQ function. Pathogenic biallelic PIGQ variants were associated with increased mortality. Epileptic seizures, axial hypotonia, developmental delay and multiple congenital anomalies were consistently observed. Seizure onset occurred between 2.5 months and 7 months of age and varied from treatable seizures to recurrent episodes of status epilepticus. Gastrointestinal issues were common and severe, two affected individuals had midgut volvulus requiring surgical correction. Cardiac anomalies including arrythmias were observed. Flow cytometry using granulocytes and fibroblasts from affected individuals showed reduced expression of glycosylphosphatidylinositol (GPI)‐anchored proteins. Transfection of wildtype PIGQ cDNA into patient fibroblasts rescued this phenotype. We expand the phenotypic spectrum of PIGQ‐related disease and provide the first functional evidence in human cells of defective GPI‐anchoring due to pathogenic variants in PIGQ.

中文翻译：

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PIGQ 中双等位基因致病性变异引起的早期婴儿癫痫性脑病：七名新受试者的报告和文献回顾。

我们调查了来自 6 个家庭的 7 名儿童，以扩大与早期婴儿癫痫性脑病相关的表型谱，该病由磷脂酰肌醇聚糖锚定生物合成类 Q ( PIGQ ) 基因的双等位基因致病变异引起。受影响的儿童都是通过临床或研究外显子组测序确定的。对包括 EEG 和 MRI 在内的临床数据进行了全面审查，并进行了流式细胞术和转染实验以研究 PIGQ 功能。致病性双等位基因PIGQ变异与死亡率增加有关。一直观察到癫痫发作、轴向肌张力减退、发育迟缓和多种先天性异常。癫痫发作发生在 2.5 个月到 7 个月之间，从可治疗的癫痫发作到反复发作的癫痫持续状态不等。胃肠道问题很常见且很严重，两名受影响的人患有需要手术矫正的中肠扭转。观察到包括心律失常在内的心脏异常。使用受影响个体的粒细胞和成纤维细胞的流式细胞术显示糖基磷脂酰肌醇 (GPI) 锚定蛋白的表达减少。将野生型PIGQ cDNA 转染到患者成纤维细胞中可挽救该表型。我们扩展了PIGQ的表型谱相关疾病，并提供了人类细胞中由于PIGQ 致病性变异导致 GPI 锚定缺陷的第一个功能证据。