Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 23, Issue 4, Pages -Publisher
MDPI
DOI: 10.3390/ijms23042278
Keywords
whole exome sequencing; OMICs; hidradenitis suppurativa; PASH; PAPASH; SAPHO
Funding
- Institute for Maternal and Child Health IRCCS Burlo Garofolo/Italian Ministry of Health [RC03/20, RC16/2018]
- grant Interreg Italia-Slovenia [ISE-EMH 07/2019]
- Biomolecular Analyses for Tailored Medicine in AcneiNversa (BATMAN) project - ERA PerMed [JTC_2018]
- Brazilian National Council for scientific and Technological Development CNPq [430353/2018-9]
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Unravelling the molecular basis of multifactorial disorders requires new genomic analysis tools that focus on disrupted pathways rather than associated gene variants, as association studies have limitations in understanding the interactions between disease-causing variants. In this study, Variant Enrichment Analysis (VEA) was developed and applied to identify novel pathways altered in patients with complex autoinflammatory skin disorders.
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 (n = 9), 3 of whom are overlapping with SAPHO) and PAPASH (n = 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.
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