Department of Bioinformatics - BiGCaT, NUTRIM, Maastricht University, Maastricht, 6229 ER, The Netherlands.
Maastricht Centre for Systems Biology (MaCSBio), Maastricht University, Maastricht, The Netherlands.
Orphanet J Rare Dis. 2023 Oct 24;18(1):335. doi: 10.1186/s13023-023-02953-6.
22q11.2 Deletion Syndrome (22q11DS) is a genetic disorder characterized by the deletion of adjacent genes at a location specified as q11.2 of chromosome 22, resulting in an array of clinical phenotypes including autistic spectrum disorder, schizophrenia, congenital heart defects, and immune deficiency. Many characteristics of the disorder are known, such as the phenotypic variability of the disease and the biological processes associated with it; however, the exact and systemic molecular mechanisms between the deleted area and its resulting clinical phenotypic expression, for example that of neuropsychiatric diseases, are not yet fully understood.
Using previously published transcriptomics data (GEO:GSE59216), we constructed two datasets: one set compares 22q11DS patients experiencing neuropsychiatric diseases versus healthy controls, and the other set 22q11DS patients without neuropsychiatric diseases versus healthy controls. We modified and applied the pathway interaction method, originally proposed by Kelder et al. (2011), on a network created using the WikiPathways pathway repository and the STRING protein-protein interaction database. We identified genes and biological processes that were exclusively associated with the development of neuropsychiatric diseases among the 22q11DS patients. Compared with the 22q11DS patients without neuropsychiatric diseases, patients experiencing neuropsychiatric diseases showed significant overrepresentation of regulated genes involving the natural killer cell function and the PI3K/Akt signalling pathway, with affected genes being closely associated with downregulation of CRK like proto-oncogene adaptor protein. Both the pathway interaction and the pathway overrepresentation analysis observed the disruption of the same biological processes, even though the exact lists of genes collected by the two methods were different.
Using the pathway interaction method, we were able to detect a molecular network that could possibly explain the development of neuropsychiatric diseases among the 22q11DS patients. This way, our method was able to complement the pathway overrepresentation analysis, by filling the knowledge gaps on how the affected pathways are linked to the original deletion on chromosome 22. We expect our pathway interaction method could be used for problems with similar contexts, where complex genetic mechanisms need to be identified to explain the resulting phenotypic plasticity.
22q11.2 缺失综合征（22q11DS）是一种遗传疾病，其特征是 22 号染色体 q11.2 位置上相邻基因的缺失，导致一系列临床表型，包括自闭症谱系障碍、精神分裂症、先天性心脏缺陷和免疫缺陷。该疾病的许多特征已为人所知，例如疾病的表型可变性及其相关的生物学过程；然而，对于缺失区域与其导致的临床表型表达之间的确切和系统的分子机制，例如神经精神疾病，仍未完全理解。
使用先前发表的转录组学数据（GEO：GSE59216），我们构建了两个数据集：一组将 22q11DS 患者中患有神经精神疾病的患者与健康对照组进行比较，另一组将 22q11DS 患者中没有神经精神疾病的患者与健康对照组进行比较。我们修改并应用了 Kelder 等人（2011 年）提出的通路相互作用方法，该方法基于 WikiPathways 通路库和 STRING 蛋白质-蛋白质相互作用数据库创建的网络。我们确定了与 22q11DS 患者神经精神疾病发展相关的基因和生物学过程，这些基因和生物学过程在 22q11DS 患者中是特有的。与没有神经精神疾病的 22q11DS 患者相比，患有神经精神疾病的患者表现出明显的调控基因参与自然杀伤细胞功能和 PI3K/Akt 信号通路的过度表达，受影响的基因与 CRK 样原癌基因适配器蛋白的下调密切相关。尽管两种方法收集的基因列表不同，但通路相互作用和通路过表达分析都观察到了相同的生物学过程的破坏。
使用通路相互作用方法，我们能够检测到一个可能解释 22q11DS 患者神经精神疾病发展的分子网络。这样，我们的方法可以补充通路过表达分析，填补受影响途径与染色体 22 上原始缺失之间的关联的知识空白。我们希望我们的通路相互作用方法可以用于类似背景的问题，在这些问题中需要确定复杂的遗传机制来解释由此产生的表型可塑性。
