Mapping of two genetic loci for autosomal dominant hidradenitis suppurativa

Abstract

Hidradenitis suppurativa (HS) is a severe and debilitating skin condition that is relatively common in the population. In many cases, there is a strong family history showing autosomal dominant inheritance with incomplete penetrance. We identified several large kindreds from the United Kingdom and Ireland showing dominant transmission and carried out two genome‐wide scans by genetic linkage analysis with 400 closely spaced microsatellite markers.This resulted in the identification of two separate genetic loci that show statistically significant linkage with HS. Marker D19S414 gave a significant log‐of‐the‐odds (LOD) score of 3.66 in a single kindred and represents robust genetic linkage. Recombination with markers D19S911 and D19S1170 limited the interval to a 16.5‐Mb region on chromosome 19, containing at least 35 known or strongly predicted genes. Many of these are transcription factors thought to be involved in modulation of the immune system, which may be consistent with HS. Two additional kindreds did not map to this locus but instead showed linkage to marker D6S290, giving a maximum combined 2‐point LOD score of 4.0 with no recombination. Visible recombinants narrowed this disease interval to a 1.48‐Mb region between D6S440 and D6S441 on chromosome 6q25.1‐25.2 containing six genes. We have already screened a large number of exons in both loci for mutations without identifying any obvious mutations.The eventual identification of genes causing HS will shed light on the pathomechanisms underlying inherited forms of the disease and, ultimately, will set the scene for rational design of therapies aimed at treating the root causes of this disorder.