Transcriptomic analysis of the major orphan ichthyosis subtypes reveals shared immune and barrier signatures
Background: Preliminary work suggested upregulation of inflammatory pathways in patients with common forms of ichthyosis. However, a comprehensive characterization of skin from various ichthyosis subtypes is unavailable, precluding development of targeted treatments. Objective: To characterize the immune and barrier profiles of common and subtype-specific skin transcriptomes in a large group of ichthyosis patients. Methods: We performed the first global RNA-seq analysis in 54 ichthyosis patients (7 Netherton syndrome/NS, 13 epidermolytic ichthyosis/EI, 16 lamellar ichthyosis/LI, 18 congenital ichthyosiform erythroderma/CIE) and 40 healthy controls using RNA-seq. Differentially expressed genes (DEGs) were defined based on fold changes/FCH>2 and false discovery rate/FDR<0.05 criteria. Results: We found robust and significant Th22/Th17 skewing in all subtypes (e.g. IL-17A/C/F, S100A7/8/9/12; p<0.001) with modest changes in Th2 pathway, primarily in NS. Across all subtypes (less evident in EI), lipid metabolism and barrier junction markers were downregulated (e.g. FA2H, CDH10/11/12/2; p<0.05), whereas epidermal cornification and proliferation measures were upregulated (e.g. SPRR1A/1B/2C/2G, EREG; p<0.05). Limitations: Although the largest ichthyosis cohort to date, sample size by subtype is still limited due to rarity. Conclusion: Our findings suggest that the common ichthyosis variants share aberrations in Th17/Th22, and barrier function, with minimal Th2 modulation. This may help elucidate the pathogeneses of these subtypes and inform the development of subtype-specific treatments.