Department of Advanced Diagnostics, Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", 34137 Trieste, Italy.
Dermatology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy.
Int J Mol Sci. 2022 Feb 18;23(4):2278. doi: 10.3390/ijms23042278.
The challenge of unravelling the molecular basis of multifactorial disorders nowadays cannot rely just on association studies searching for potential causative variants shared by groups of patients and not present in healthy individuals; indeed, association studies have as a main limitation the lack of information on the interactions between the disease-causing variants. Thus, new genomic analysis tools focusing on disrupted pathways rather than associated gene variants are required to better understand the complexity of a disease. Therefore, we developed the Variant Enrichment Analysis (VEA) workflow, a tool applicable for whole exome sequencing data, able to find differences between the numbers of genetic variants in a given pathway in comparison with a reference dataset. In this study, we applied VEA to discover novel pathways altered in patients with complex autoinflammatory skin disorders, namely PASH ( = 9), 3 of whom are overlapping with SAPHO) and PAPASH ( = 3). With this approach we have been able to identify pathways related to neutrophil and endothelial cells homeostasis/activations, as disrupted in our patients. We hypothesized that unregulated neutrophil transendothelial migration could elicit increased neutrophil infiltration and tissue damage. Based on our findings, VEA, in our experimental dataset, allowed us to predict novel pathways impaired in subjects with autoinflammatory skin disorders.
如今，要阐明多因素疾病的分子基础，仅依靠寻找患者群体中存在但健康个体中不存在的潜在致病变异的关联研究是远远不够的；事实上，关联研究的主要局限性在于缺乏对致病变异之间相互作用的信息。因此，需要新的基因组分析工具，重点关注被破坏的途径，而不是相关的基因变异，以更好地理解疾病的复杂性。因此，我们开发了 Variant Enrichment Analysis (VEA) 工作流程，这是一种适用于全外显子组测序数据的工具，能够发现给定途径中的遗传变异数量与参考数据集之间的差异。在这项研究中，我们应用 VEA 来发现复杂的自身炎症性皮肤疾病患者中改变的新途径，即 PASH（=9），其中 3 例与 SAPHO 重叠）和 PAPASH（=3）。通过这种方法，我们能够确定与中性粒细胞和内皮细胞稳态/激活相关的途径在我们的患者中受到干扰。我们假设不受调节的中性粒细胞跨内皮迁移可能会引起中性粒细胞浸润和组织损伤增加。基于我们的发现，VEA 在我们的实验数据集允许我们预测自身炎症性皮肤疾病患者中受损的新途径。
