Distribution of hidradenitis suppurativa monogenic etiologies in a racially diverse specialty clinic cohort

Hidradenitis suppurativa (HS) is an inflammatory skin disease that disproportionally affects African American women and has many unmet needs. Disease mutations have been reported in three γ-secretase genes (NSCTN, PSENEN, and PSEN1) and PSTPIP1. The population relevance of these monogenic etiologies is incompletely characterized. Previous studies, limited in size and ancestral diversity, utilized small cohorts of either European or Asian ancestry, yielding unstable prevalence estimates (0%-6%) that may not be generalizable to other populations. We aimed to determine the prevalence of HS monogenic etiologies in a large multiracial HS cohort. We performed exome sequencing of 219 HS research participants using standard sample and variant quality thresholds. We used a validated ancestry classification model to determine genetic ancestry of participants. Mutations, defined as having a maximum allele frequency less than .001 in large diverse databases, were extracted for NSCTN, PSENEN, PSEN1 and PSTPIP1. Genetically-defined ancestry indicates 79% of participants have African admixture, 7% have South Asian ancestry, and 14% are genetically-defined Caucasian. We identified seven mutations, notably, 6/7 were in those with genetic ancestries hitherto unrepresented in HS genetic studies. We identified two loss-of-function mutations in NCSTN (p.D443fs; splice site c.148-1G>T), and five missense mutations in PSEN1 (p.P355S; p.G206A) and PSTPIP1 (p.R320Q; p.P283L, p.R44C). PSEN1 mutation p.G206A is annotated as pathogenic in ClinVar. Our preliminary estimate for the prevalence of HS monogenic etiologies in a racially diverse cohort is 3%. Pathogenicity remains to be determined for these mutations, like many others reported in prior HS genetic studies. A lack of in vitro systems to efficiently determine the biological effects of mutations in these genes is a major barrier to advancing precision medicine in HS.