Somatic mutations in NEK9 drive comedogenesis

Summary: Abstract Body: Comedogenesis is a process by which keratinaceous debris is produced in hair follicles, leading to follicular occlusion. We previously reported somatic variants in NEK9 cause nevus comedonicus, a rare disorder identifiable at birth featuring severe cystic comedones, but the cause of comedogenesis in acquired disorders has remained less clear. Here we propose somatic mutation as an underlying cause of comedogenesis across different diseases, and a subsequent shared biologic underpinning to comedo formation in these unrelated contexts. To identify possible shared genetic drivers of comedogenesis, we collected fresh tissue from epidermal inclusion cysts (EICs), a common lesion comprised of a single comedo with an underlying cyst. We sequenced saliva and lesional tissue from 14 EICs and identified somatic, rare, damaging variants in the NEK9 gene in 12 samples. Interestingly, 9 of the 12 variants were identical to those reported in nevus comedonicus. The 3 novel variants localized within 19 amino acids adjacent to those previously identified, suggesting a potential specific role for NEK9 function within the hair follicle. It has been proposed that comedogenesis occurs due to dysregulation of specific keratinocyte populations within the follicle, though the driver for such dysregulation has not been identified. We identified ectopic expression of the epidermal differentiation marker Keratin 10 within the cyst wall of EICs, consistent with a loss of follicular specification. The identification of somatic NEK9 variants in 85% of EICs, a postnatally acquired lesion, as well as in nevus comedonicus, a severe comedonal disorder that develops in utero, supports NEK9 variants as robust driver of comedogenesis both during early follicular development and during adulthood, a topic actively under investigation by our group. More broadly, our work highlights the underestimated contribution of mutagenesis to common and acquired dermatologic diseases not previously considered genetic in origin. Katharine Ellis¹, Peggy Myung², Jeffrey M. Cohen², Keith Choate² 1. Genetics, Yale University School of Medicine, New Haven, CT, United States. 2. Dermatology, Yale University School of Medicine, New Haven, CT, United States. Genetic Disease, Gene Regulation, Gene Therapy & Epigenetics