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

Brandão, Lucas André Cavalcanti ; Moura, Ronald Rodrigues de ; Marzano, Angelo Valerio ; Moltrasio, Chiara ; Tricarico, Paola Maura ; Crovella, Sergio

International journal of molecular sciences, 2022-02, Vol.23 (4), p.2278 [Periódico revisado por pares]

Switzerland: MDPI AG

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  • Título:
    Variant Enrichment Analysis to Explore Pathways Functionality in Complex Autoinflammatory Skin Disorders through Whole Exome Sequencing Analysis
  • Autor: Brandão, Lucas André Cavalcanti ; Moura, Ronald Rodrigues de ; Marzano, Angelo Valerio ; Moltrasio, Chiara ; Tricarico, Paola Maura ; Crovella, Sergio
  • Assuntos: Acne ; Biosynthesis ; Complexity ; Datasets ; Endothelial cells ; Genetic diversity ; Genomes ; Genomic analysis ; hidradenitis suppurativa ; Homeostasis ; Leukocytes (neutrophilic) ; Mutation ; OMICs ; PAPASH ; PASH ; Pathogenesis ; Patients ; SAPHO ; Sequence analysis ; Skin diseases ; whole exome sequencing ; Workflow
  • É parte de: International journal of molecular sciences, 2022-02, Vol.23 (4), p.2278
  • Notas: These authors contributed equally to this work.
  • Descrição: 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.
  • Editor: Switzerland: MDPI AG
  • Idioma: Inglês
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  • Realização: ABCD-USP USP   Logos de Redes Sociais: Freepik

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