In the rapidly growing group of rare genetic disorders, data scarcity demands an intelligible use of available data, in order to improve understanding of underlying pathophysiology. We hypothesize, based on the principle that clinical similarities may be indicative of shared pathophysiology, that determining phenotypic specificity could provide unsuspected insights in pathophysiology of rare genetic disorders. We explored our hypothesis by studying subunit deficiencies of the conserved oligomeric Golgi (COG) complex, a subgroup of congenital disorders of glycosylation (CDG). In this systematic data assessment, all 45 reported patients with COG‐CDG were included. The vocabulary of the Human Phenotype Ontology was used to annotate all phenotypic features and to assess occurrence in other genetic disorders. Gene occurrence ratios were calculated by dividing the frequency in the patient cohort over the number of associated genes, according to the Human Phenotype Ontology. Prioritisation based on phenotypic specificity was highly informative and captured phenotypic features commonly associated with glycosylation disorders. Moreover, it captured features not seen in any other glycosylation disorder, among which episodic fever, likely reflecting underappreciated other cellular functions of the COG complex. Interestingly, the COG complex was recently implicated in the autophagy pathway, as are more than half of the genes underlying disorders that present with episodic fever. This suggests that whereas many phenotypic features in these patients are caused by disrupted glycosylation, episodic fever might be caused by disrupted autophagy. Thus, we here demonstrate support for our hypothesis that determining phenotypic specificity could facilitate understanding of pathophysiology in rare genetic disorders.

中文翻译：

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假设：确定表型特异性有助于理解罕见遗传疾病的病理生理学。

在快速增长的罕见遗传疾病组中，数据稀缺需要对可用数据进行可理解的使用，以提高对潜在病理生理学的理解。我们假设，基于临床相似性可能表明共同病理生理学的原则，确定表型特异性可以为罕见遗传疾病的病理生理学提供意想不到的见解。我们通过研究保守的寡聚高尔基体 (COG) 复合体的亚基缺陷来探索我们的假设，该复合体是先天性糖基化疾病 (CDG) 的一个亚组。在这个系统的数据评估中，所有 45 名报告的 COG-CDG 患者都包括在内。人类表型本体的词汇用于注释所有表型特征并评估其他遗传疾病的发生。根据人类表型本体论，通过将患者队列中的频率除以相关基因的数量来计算基因发生率。基于表型特异性的优先级具有高度信息性，并捕获了通常与糖基化障碍相关的表型特征。此外，它捕获了在任何其他糖基化疾病中都没有看到的特征，其中包括发作性发热，这可能反映了 COG 复合物的其他细胞功能未被充分认识。有趣的是，COG 复合物最近与自噬途径有关，超过一半的基因与发作性发热相关的疾病相关。这表明，虽然这些患者的许多表型特征是由糖基化破坏引起的，但发作性发热可能是由自噬破坏引起的。因此，