Identification of Novel Genetic Risk Variants Associated with Hidradenitis Suppurativa in an Exome Sequencing Cohort of 92,455 Individuals

Introduction: Hidradenitis suppurativa (HS) is a prevalent and persistent inflammatory skin disorder, lacking a known cure or effective biomarkers for early diagnosis at present. The genetic determinants of HS have not been fully documented, but it is believed to result from a combination of genetic and environmental factors. Methods: To identify relevant HS gene variants in sporadic HS patients, this study utilized longitudinal electronic health records (EHRs) and whole-exome sequencing. DNA exome sequencing data from 92,455 participant samples in the MyCode biobank, linked to Geisinger’s EHR, were analyzed. This cohort included 1,092 HS cases and 91,363 healthy controls. The MyCode EHR has a median longitudinal follow-up of 15 years per participant, with an average of 87 clinical encounters, 687 laboratory tests, and 7 procedures. Results: There were 1,092 (901 females and 191 males) participants aged 14–89 years (median 47 years) with HS (L73.2), indicating a 1.18% prevalence and accounting for a 4.7:1 female-to-male ratio among the individuals presenting for clinical care. γ-secretase complex, syndromic, and autoinflammatory gene variants were assessed. Potential pathogenic variants were identified among 66 individuals in the HS genes studied. Molecularly, the estimated HS variant prevalence was 1:1,400 in the cohort, 12.3% of variant carriers had HS diagnosis in EHR. Conclusions: Using longitudinal EHR data, genomic screening identified HS-associated gene variants in a defined group of sporadic HS patients to augment the clinical diagnosis, particularly in cases of ambiguity. Based on this study, the field of skin disorders can benefit from a personalized approach to HS diagnosis using large-scale sequencing.