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Variant Enrichment Analysis to Explore Pathways Functionality in Complex Autoinflammatory Skin Disorders through Whole Exome Sequencing Analysis

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...

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Autores principales: Brandão, Lucas André Cavalcanti, de Moura, Ronald Rodrigues, Marzano, Angelo Valerio, Moltrasio, Chiara, Tricarico, Paola Maura, Crovella, Sergio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8877088/
https://www.ncbi.nlm.nih.gov/pubmed/35216413
http://dx.doi.org/10.3390/ijms23042278
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author Brandão, Lucas André Cavalcanti
de Moura, Ronald Rodrigues
Marzano, Angelo Valerio
Moltrasio, Chiara
Tricarico, Paola Maura
Crovella, Sergio
author_facet Brandão, Lucas André Cavalcanti
de Moura, Ronald Rodrigues
Marzano, Angelo Valerio
Moltrasio, Chiara
Tricarico, Paola Maura
Crovella, Sergio
author_sort Brandão, Lucas André Cavalcanti
collection PubMed
description 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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spelling pubmed-88770882022-02-26 Variant Enrichment Analysis to Explore Pathways Functionality in Complex Autoinflammatory Skin Disorders through Whole Exome Sequencing Analysis Brandão, Lucas André Cavalcanti de Moura, Ronald Rodrigues Marzano, Angelo Valerio Moltrasio, Chiara Tricarico, Paola Maura Crovella, Sergio Int J Mol Sci Article 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. MDPI 2022-02-18 /pmc/articles/PMC8877088/ /pubmed/35216413 http://dx.doi.org/10.3390/ijms23042278 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Brandão, Lucas André Cavalcanti
de Moura, Ronald Rodrigues
Marzano, Angelo Valerio
Moltrasio, Chiara
Tricarico, Paola Maura
Crovella, Sergio
Variant Enrichment Analysis to Explore Pathways Functionality in Complex Autoinflammatory Skin Disorders through Whole Exome Sequencing Analysis
title Variant Enrichment Analysis to Explore Pathways Functionality in Complex Autoinflammatory Skin Disorders through Whole Exome Sequencing Analysis
title_full Variant Enrichment Analysis to Explore Pathways Functionality in Complex Autoinflammatory Skin Disorders through Whole Exome Sequencing Analysis
title_fullStr Variant Enrichment Analysis to Explore Pathways Functionality in Complex Autoinflammatory Skin Disorders through Whole Exome Sequencing Analysis
title_full_unstemmed Variant Enrichment Analysis to Explore Pathways Functionality in Complex Autoinflammatory Skin Disorders through Whole Exome Sequencing Analysis
title_short Variant Enrichment Analysis to Explore Pathways Functionality in Complex Autoinflammatory Skin Disorders through Whole Exome Sequencing Analysis
title_sort variant enrichment analysis to explore pathways functionality in complex autoinflammatory skin disorders through whole exome sequencing analysis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8877088/
https://www.ncbi.nlm.nih.gov/pubmed/35216413
http://dx.doi.org/10.3390/ijms23042278
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