Inherited glycosylphosphatidylinositol deficiency disorders (IGDs) are a group of rare multisystem disorders arising from pathogenic variants in glycosylphosphatidylinositol anchor pathway (GPI-AP) genes. Despite associating 24 of at least 31 GPI-AP genes with human neurogenetic disease, prior reports are limited to single genes without consideration of the GPI-AP as a whole and with limited natural history data. In this multinational retrospective observational study, we systematically analyse the molecular spectrum, phenotypic characteristics, and natural history of 83 individuals from 75 unique families with IGDs, including 70 newly reported individuals: the largest single cohort to date. Core clinical features were developmental delay or intellectual disability (DD/ID, 90%), seizures (83%), hypotonia (72%), and motor symptoms (64%). Prognostic and biologically significant neuroimaging features included cerebral atrophy (75%), cerebellar atrophy (60%), callosal anomalies (57%), and symmetric restricted diffusion of the central tegmental tracts (60%). Sixty-one individuals had multisystem involvement including gastrointestinal (66%), cardiac (19%), and renal (14%) anomalies. Though dysmorphic features were appreciated in 82%, no single dysmorphic feature had a prevalence >30%, indicating substantial phenotypic heterogeneity. Follow-up data were available for all individuals, 15 of whom were deceased at the time of writing. Median age at seizure onset was 6 months. Individuals with variants in synthesis stage genes of the GPI-AP exhibited a significantly shorter time to seizure onset than individuals with variants in transamidase and remodelling stage genes of the GPI-AP (P=0.046). Forty individuals had intractable epilepsy. The majority of individuals experienced delayed or absent speech (95%); motor delay with non-ambulance (64%); and severe-to-profound DD/ID (59%). Individuals with a developmental epileptic encephalopathy (51%) were at greater risk of intractable epilepsy (P=0.003), non-ambulance (P=0.035), ongoing enteral feeds (P<0.001), and cortical visual impairment (P=0.007). Serial neuroimaging showed progressive cerebral volume loss in 87.5% and progressive cerebellar atrophy in 70.8%, indicating a neurodegenerative process. Genetic analyses identified 93 unique variants (106 total), including 22 novel variants. Exploratory analyses of genotype-phenotype correlations using unsupervised hierarchical clustering identified novel genotypic predictors of clinical phenotype and long-term outcome with meaningful implications for management. In summary, we expand both the mild and severe phenotypic extremities of the IGDs; provide insights into their neurological basis; and, vitally, enable meaningful genetic counselling for affected individuals and their families.

中文翻译：

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遗传性糖基磷脂酰肌醇缺乏症的临床和遗传谱

遗传性糖基磷脂酰肌醇缺乏症 (IGD) 是一组罕见的多系统疾病，由糖基磷脂酰肌醇锚定通路 (GPI-AP) 基因的致病性变异引起。尽管至少 31 个 GPI-AP 基因中的 24 个与人类神经遗传疾病相关，但之前的报道仅限于单个基因，没有考虑 GPI-AP 作为一个整体，并且自然史数据也有限。在这项跨国回顾性观察研究中，我们系统地分析了来自 75 个独特 IGD 家族的 83 名个体的分子谱、表型特征和自然史，其中包括 70 名新报告的个体：迄今为止最大的单一队列。核心临床特征是发育迟缓或智力障碍（DD/ID，90%）、癫痫发作（83%）、肌张力低下（72%）和运动症状（64%）。具有预后和生物学意义的神经影像学特征包括脑萎缩（75%）、小脑萎缩（60%）、胼胝体异常（57%）和中央被盖束对称性受限扩散（60%）。61 人有多系统受累，包括胃肠道（66%）、心脏（19%）和肾脏（14%）异常。尽管82%的人认识到畸形特征，但没有单一畸形特征的患病率>30%，这表明显着的表型异质性。所有个人的后续数据均已公布，其中 15 人在撰写本文时已去世。癫痫发作的中位年龄为 6 个月。与具有 GPI-AP 转酰胺酶和重塑阶段基因变异的个体相比，具有 GPI-AP 合成阶段基因变异的个体表现出癫痫发作的时间显着更短 (P=0.046)。四十人患有顽固性癫痫。大多数人都经历过言语迟缓或缺席（95%）；非救护车导致运动延迟（64%）；以及重度至重度 DD/ID (59%)。患有发育性癫痫性脑病的个体（51%）患顽固性癫痫（P=0.003）、非救护车（P=0.035）、持续肠内喂养（P<0.001）和皮质视力障碍（P=0.007）的风险更大。连续神经影像显示 87.5% 的人出现进行性脑容量减少，70.8% 的人出现进行性小脑萎缩，表明存在神经退行性过程。遗传分析发现了 93 个独特变异（总共 106 个），其中包括 22 个新变异。使用无监督的层次聚类对基因型-表型相关性进行探索性分析，确定了临床表型和长期结果的新基因型预测因子，对管理具有有意义的影响。总之，我们扩展了 IGD 的轻度和重度表型末端；提供对其神经学基础的见解；更重要的是，为受影响的个人及其家人提供有意义的遗传咨询。