# Rare Filaggrin Variants Are Associated with Pustular Skin Diseases in Asians

## TL;DR

Rare variations in the filaggrin gene are linked to pustular skin diseases like pustular psoriasis and a type of immunodeficiency syndrome in Asian patients.

## Contribution

The study identifies novel and previously unclassified rare filaggrin gene variants associated with pustular skin diseases in Asian populations.

## Key findings

- 76% of AOID-PR patients and 58% of PP patients carried rare filaggrin gene variants.
- Two of the identified filaggrin variants were entirely novel and not previously documented in pustular disorders.
- Certain filaggrin variants reduced FLG levels similarly to a known pathogenic variant.

## Abstract

Reactive pustular eruptions (RPEs) can manifest in a variety of conditions, including pustular psoriasis (PP) and adult-onset immunodeficiency syndrome due to anti-interferon-γ autoantibody (AOID). These RPEs can be attributed to different causes, one of which is genetic factors. However, the genetic basis for pustular skin diseases remains poorly understood. In our study, we conducted whole-exome sequencing on a cohort of 17 AOID patients with pustular reactions (AOID-PR) and 24 PP patients. We found that 76% and 58% of the AOID-PR and PP patients, respectively, carried rare genetic variations within the filaggrin (FLG) gene family. A total of 12 out of 21 SNPs on FLG had previously received clinical classifications, with only p.Ser2706Ter classified as pathogenic. In contrast, none of the FLG3 SNPs identified in this study had prior clinical classifications. Overall, these variations had not been previously documented in cases of pustular disorders, and two of them were entirely novel discoveries. Immunohistochemical analysis of skin biopsies revealed that FLG variants like p.Ser860Trp, p.Gly3903Ter, p.Gly2440Glu, and p.Glu2133Asp caused reductions in FLG levels similar to the pathogenic FLG p.Ser2706Ter. These results highlight rare FLG variants as potential novel genetic risk factors contributing to pustule formation in both AOID and PP.