Variant Enrichment Analysis to Explore Pathways Functionality in Complex Autoinflammatory Skin Disorders through...

Area of Science:

• Genomics
• Dermatology
• Systems Biology

Background:

• Multifactorial disorders require advanced genomic analysis beyond traditional association studies.
• Understanding gene variant interactions is crucial for complex disease research.
• Existing methods lack focus on disrupted biological pathways.

Purpose of the Study:

• To develop and apply a novel workflow, Variant Enrichment Analysis (VEA), for whole exome sequencing data.
• To identify altered biological pathways in patients with autoinflammatory skin disorders.
• To uncover the molecular underpinnings of conditions like PASH and PAPASH.

Main Methods:

• Developed the Variant Enrichment Analysis (VEA) workflow for whole exome sequencing data.
• Compared genetic variant enrichment in specific pathways between patient cohorts and reference datasets.
• Applied VEA to cohorts of patients with PASH (n=9) and PAPASH (n=3).

Main Results:

• Identified disrupted pathways related to neutrophil homeostasis and activation.
• Identified disrupted pathways related to endothelial cell homeostasis and activation.
• Highlighted the potential role of dysregulated neutrophil transendothelial migration in disease pathogenesis.

Conclusions:

• VEA is an effective tool for discovering novel, disrupted pathways in complex diseases.
• Neutrophil and endothelial cell pathways are significantly altered in the autoinflammatory skin disorders studied.
• Findings suggest VEA can predict impaired pathways in subjects with complex autoinflammatory conditions.