O07 Solar urticaria is associated with novel rare missense variants in <i>ACACA</i>

Abstract Introduction and aims Solar urticaria (SU) is a rare, poorly understood photodermatosis characterized by inappropriate mast cell degranulation following cutaneous exposure to sunlight. Based on a lack of Mendelian inheritance in families and its onset in adulthood with limited impact on reproductive fitness, SU is likely a complex trait whose development is determined by genetic and environmental factors. Its rarity and unusual phenotype, which constitutes an extreme aberration of physiological responses to sunlight, imply that its genetic architecture may be underpinned by rare, highly penetrant and deleterious variants. To investigate this, we performed a case–control whole-exome sequencing gene association study in SU. Methods Forty-six patients of European ancestry with phototest-confirmed SU underwent whole-exome sequencing. Healthy control whole exomes (n = 971) were derived from the 1958 British Birth Cohort. Following quality control, joint variant calling and variant filtering to retain rare, high-impact variants, burden testing was performed. Sanger sequencing and bioinformatic resources were used to validate and explore identified genes/variants. Results Burden testing revealed exome-wide significant enrichment of rare, high-impact variants in ACACA among SU cases (P = 4.7 × 10−7). This gene encodes acetyl-coenzyme A carboxylase alpha, an enzyme that catalyses the rate-limiting step in de novo lipogenesis. Six of 46 SU cases carried rare, heterozygous missense variants in ACACA compared with 3 of 971 controls. Sanger sequencing validated the presence of these variants in ACACA. Structural analyses demonstrated that ACACA variants were predicted to decrease protein stability. Reanalysis of single-cell RNA sequencing data from skin confirmed ACACA expression in all cell types, including mast cells. Conclusions Enrichment of rare, deleterious ACACA variants among patients with SU suggests a role for altered lipid metabolism, potentially affecting mast cell function, in SU pathogenesis. Characterization of lipid-mediated disease mechanisms in SU should form the basis of future investigations.