837 Untargeted lipidomics and transcriptomics suggest role of ceramide increases in congenital ichthyosis phenotypes

Congenital ichthyoses (CI), inherited scaling disorders, have an impaired epidermal barrier, but ceramide (Cer) changes are poorly understood. Using untargeted lipidomics, we compared Cer profiles of tape-stripped skin from 77 patients with 6 subtypes CI and 19 matched controls. In CI, 636 species were found, including 24 low-abundance Cers not in healthy skin. 221 significantly (>2-fold; adj. p<0.01) reduced overall each subtype vs. controls, especially abundant, very-long ultra-long chain fatty acids (FAs) phyto- or dihydrosphingosine sphingoid bases (LCBs) ≥20 carbons (C20). 156 increased low abundance, C16-21 FA chains sphingosine diene LCBs shorter carbon length (≤C18). Lamellar ichthyosis (LI) had the highest increased:decreased ratio (1.05) congenital ichthyosiform erythroderma (CIE) lowest (0.48) (p<0.006). Decreased EOS weakly correlated Ichthyosis Area Severity Index-Scale/IASI-S, IASI-Erythema/-E, transepidermal water loss/TEWL. contrast, moderately severity, showed a distinct pattern Cer-to-severity correlations (eg, Netherton syndrome for IASI-E [r=0.55], LI IASI-S [r=0.4], EI TEWL [r=-0.4], all p<0.001). We integrated 54 biopsied RNA-Seq data same subjects lipidomics data. Increased negatively SPTLC3,which promotes non-C18 LCB synthesis, genes mutated CIE. positively TGM1 (mutated LI), ceramidase genes, SPTLC2, which generates C18 senses excess Cer. These multimodal define landscape suggest key role increases phenotypes.