The genetic basis for most patients with pustular skin disease remains elusive

Abstract

SummaryBackground Rare variants in the genes IL36RN, CARD14 and AP1S3 have been identified to cause or contribute to pustular skin diseases, primarily generalized pustular psoriasis (GPP). Objectives To better understand the disease relevance of these genes, we screened our cohorts of patients with pustular skin diseases [primarily GPP and palmoplantar pustular psoriasis (PPP)] for coding changes in these three genes. Carriers of single heterozygous IL36RN mutations were screened for a second mutation in IL36RN. Methods Coding exons of IL36RN, CARD14 and AP1S3 were sequenced in 67 patients -61 with GPP, two with acute generalized exanthematous pustulosis and four with acrodermatitis continua of Hallopeau. We screened IL36RN and AP1S3 for intragenic copy-number variants and 258 patients with PPP for coding changes in AP1S3. Eleven heterozygous IL36RN mutations carriers were analysed for a second noncoding IL36RN mutation. Genotype-phenotype correlations in carriers/noncarriers of IL36RN mutations were assessed within the GPP cohort. Results The majority of patients (GPP, 64%) did not carry rare variants in any of the three genes. Biallelic and monoallelic IL36RN mutations were identified in 15 and five patients with GPP, respectively. Noncoding rare IL36RN variants were not identified in heterozygous carriers. The only significant genotype-phenotype correlation observed for IL36RN mutation carriers was early age at disease onset.

Coinheritance of generalized pustular psoriasis and familial Behçet‐like autoinflammatory syndrome with variants in IL36RN and TNFAIP3 in the heterozygous state

“…It is possible that maternal relatives simply have a common haplotype at IL36RN that is functioning as a hypomorphic allele, as described in TBX6 . However, in a recent study, rare non‐coding IL36RN variants were not identified in 11 heterozygous carriers …”

“…However, single heterozygous variants of the IL36RN gene in some cases with GPP and homozygous variants in unaffected individuals indicate a complex mode of inheritance instead of a recessive Mendelian inheritance in GPP with IL36RN variants. Moreover, segregation analyses confirm that the probands have inherited the disease allele of IL36RN or AP1S3 from an unaffected parent, which suggests the presence of unidentified environmental triggers, a modifier locus or an oligogenic inheritance . Mossner et al .…”

The heterogeneous mutational landscape of pustular psoriasis

“…The study, which is published in this issue of the BJD , confirmed the presence of substantial genetic heterogeneity. This was especially marked in PPP, where > 90% of cases were mutation negative . While this figure is slightly lower in other surveys, there is no doubt that further gene identification studies will be required to illuminate the genetic landscape of PPP and improve its molecular diagnosis.…”

“…is the thorough analysis of 11 individuals harbouring a single IL36RN mutation. It showed that none of these patients carried an exon deletion or duplication alongside the identified missense mutation . This strongly suggests the presence of modifier alleles at other loci.…”

“…Mössner et al . sought to investigate these issues through the analysis of an extended disease cohort including 61 patients with GPP, 258 with PPP and four with ACH.…”