Trio-Based Whole-Exome Sequencing Identifies Convergent Epithelial Junction-Related Pathways in Syndromic...

Hidradenitis suppurativa (HS)-related autoinflammatory syndromes, simply termed syndromic HS (sHS), represent a group of rare immune-mediated inflammatory disorders in which HS coexists with systemic or cutaneous autoinflammatory features like PASH (pyoderma gangrenosum [PG], acne, and HS), PAPASH (PASH, pyogenic arthritis), PASS (PG, acne, HS, and ankylosing spondylitis), and SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, and osteitis). In recent years, genetic studies identified several novel pathogenic variants underlying sHS; however, most investigations rely exclusively on affected individuals' sequencing, and the absence of parental genomic information limits the possibility of determining inheritance patterns.

This study aimed to address these gaps; we performed trio-based whole-exome sequencing on five individuals diagnosed with sHS and their unaffected parents.

The pathway related to epidermal adhesion and desmosome organization was the most represented across our cohort, encompassing seven genes: DSC3, DSG1, FAT1, LAMA3, MICALL2, PLEC, and TJP2. Integrin-extracellular matrix (ECM) adhesion signaling pathway, represented by ten genes (CSPG4, FERMT3, ITGA3, LAMA3, LAMA5, LIMS2, LTBP3, PLEC, TGM2, and TNC), was also retrieved. Also, variants affecting innate immune pathways, including cytokine signaling and antigen presentation, have been observed.

Our exploratory findings suggest that genetically heterogeneous variants in syndromic HS converge on biological processes involving epithelial junction organization, ECM interactions and innate immune regulation. Although not establishing a unique pathogenic mechanism, these observations identify epithelial barrier biology as a candidate pathway warranting validation in larger cohorts and functional studies.