Inborn errors of immunity in hidradenitis suppurativa

Summary: Abstract Body: Hidradenitis suppurativa (HS) is an inflammatory skin disease of terminal hair follicles. Despite many unmet needs, its genetic architecture remains understudied. Familial studies have identified four single-gene causes of HS, which belong to a larger class of Mendelian diseases of the immune system known as Inborn Errors of Immunity (IEI). IEI are increasingly diagnosed among adult with common immune-mediated diseases. We hypothesize that IEI are underdiagnosed among patients with HS. In a cohort of 270 ancestrally diverse HS research participants, we performed a diagnostic analysis of IEI genes that share clinical, cellular, or molecular features with HS (N=98). Qualifying variants (QVs) were defined as having a population frequency <0.1%, having genotype distributions consistent with known mode of inheritances, and having predicted protein-alteringe effects. QVs were identified in 29 genes in 87 participants. STAT1 exceeded a Bonferroni adjusted p-value (p=5.1x10-4) and 9 other genes reached a nominal level of significance (p<.05): PIK3R1, CDC42, NCSTN, RELA, NFKB1, FOXN1, TNFAIP3, NLRP1, JAK1. These genes enrich signaling pathways relevant to HS pathogenesis, including NOTCH, PI3K/Akt, TNF, IL17, JAK-Stat, and Leptin signaling. Interestingly, CDC42, RELA, NFKB1, FOXN1, JAK1 cause hair follicle defects in mouse models, while FOXN1 is also a cause of congenital alopecia in humans. Experimental evaluation suggests gain of function variants in STAT1, PI3KR1, or PI3KCD contribute to HS pathogenesis. These results provide preliminary evidence supporting our hypothesis and warrant further investigation. Faith Simmonds¹, Rachel Eisenberg³, Steven Cohen⁴, Joshua Milner¹, Lynn Petukhova² 1. Columbia University, New York, NY, United States. 2. New York University, New York, NY, United States. 3. Albert Einstein College of Medicine, New York, NY, United States. 4. Weill Cornell Medicine, New York, NY, United States. Genetic Disease, Gene Regulation, Gene Therapy & Epigenetics