Rare missense variants in the SH3 domain of PSTPIP1 are associated with hidradenitis suppurativa

Hidradenitis suppurativa (HS) is a chronic, debilitating skin disease estimated to affect [~]1% of the population, for which few treatment options are available. Risk factors associated with HS include smoking, obesity, and some high penetrance genetic variants. Some rare families have autosomal dominant inheritance. Previous studies have shown that rare loss-of-function variants in genes of the gamma-secretase complex, particularly nicastrin, segregate with autosomal dominant HS in some kindred. However, these gamma-secretase variants do not explain much of the overall genetic risk for HS. We performed targeted DNA sequencing of 21 candidate genes in a cohort of 117 individuals with HS to test for an increased burden of rare genetic variants. Candidates included the genes of the gamma-secretase complex, Notch signaling genes, and PSTPIP1, a known risk factor for PAPA syndrome. We discovered two pathogenic loss-of-function variants in nicastrin that to the best of our knowledge have not been described in HS before. We did not identify significant enrichment of rare missense variants in any gamma-secretase gene, further supporting that loss-of-function in gamma-secretase genes is not a common risk factor. We did, however, identify a statistically significant enrichment of rare variants in the SH3 domain of PSTPIP1. Clinical overlap between HS and PSTPIP1 syndromic features has been noted clinically. Our data suggest that there is shared genetic risk as well, and highlights the need for further population-scale HS genetic research.