{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:47:49Z","timestamp":1787028469748,"version":"build-2736575974"},"reference-count":28,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2022,2,18]],"date-time":"2022-02-18T00:00:00Z","timestamp":1645142400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Institute for Maternal and Child Health IRCCS \u201cBurlo Garofolo\/Italian Ministry of Health\u201d","award":["RC03\/20 and RC16\/ 2018"],"award-info":[{"award-number":["RC03\/20 and RC16\/ 2018"]}]},{"name":"Interreg Italia-Slovenia","award":["ISE-EMH 07\/2019"],"award-info":[{"award-number":["ISE-EMH 07\/2019"]}]},{"name":"ERA PerMed","award":["JTC_2018"],"award-info":[{"award-number":["JTC_2018"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/ijms23042278","type":"journal-article","created":{"date-parts":[[2022,2,21]],"date-time":"2022-02-21T08:18:05Z","timestamp":1645431485000},"page":"2278","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Variant Enrichment Analysis to Explore Pathways Functionality in Complex Autoinflammatory Skin Disorders through Whole Exome Sequencing Analysis"],"prefix":"10.3390","volume":"23","author":[{"given":"Lucas Andr\u00e9 Cavalcanti","family":"Brand\u00e3o","sequence":"first","affiliation":[{"name":"Department of Advanced Diagnostics, Institute for Maternal and Child Health, IRCCS \u201cBurlo Garofolo\u201d, 34137 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9112-7167","authenticated-orcid":false,"given":"Ronald Rodrigues de","family":"Moura","sequence":"additional","affiliation":[{"name":"Department of Advanced Diagnostics, Institute for Maternal and Child Health, IRCCS \u201cBurlo Garofolo\u201d, 34137 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelo Valerio","family":"Marzano","sequence":"additional","affiliation":[{"name":"Dermatology Unit, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"},{"name":"Department of Physiopathology and Transplantation, Universit\u00e0 degli Studi di Milano, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Moltrasio","sequence":"additional","affiliation":[{"name":"Dermatology Unit, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"},{"name":"Department of Medical Surgical and Health Sciences, University of Trieste, 34137 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1954-4126","authenticated-orcid":false,"given":"Paola Maura","family":"Tricarico","sequence":"additional","affiliation":[{"name":"Department of Advanced Diagnostics, Institute for Maternal and Child Health, IRCCS \u201cBurlo Garofolo\u201d, 34137 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8493-1168","authenticated-orcid":false,"given":"Sergio","family":"Crovella","sequence":"additional","affiliation":[{"name":"Biological Science Program, Department of Biological and Environmental Sciences, College of Arts and Sciences, University of Qatar, Doha 2713, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Mrozek, D. 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