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

Summary Background Rare variants in the genes IL 36 RN , CARD 14 and AP 1S3 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 IL 36 RN mutations were screened for a second mutation in IL 36 RN . Methods Coding exons of IL 36 RN , CARD 14 and AP 1S3 were sequenced in 67 patients – 61 with GPP , two with acute generalized exanthematous pustulosis and four with acrodermatitis continua of Hallopeau. We screened IL 36 RN and AP 1S3 for intragenic copy‐number variants and 258 patients with PPP for coding changes in AP 1S3 . Eleven heterozygous IL 36 RN mutations carriers were analysed for a second noncoding IL 36 RN mutation. Genotype–phenotype correlations in carriers/noncarriers of IL 36 RN 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 IL 36 RN mutations were identified in 15 and five patients with GPP , respectively. Noncoding rare IL 36 RN variants were not identified in heterozygous carriers. The only significant genotype–phenotype correlation observed for IL 36 RN mutation carriers was early age at disease onset. Additional rare CARD 14 or AP 1S3 variants were identified in 15% of IL 36 RN mutation carriers. Conclusions The identification of IL 36 RN mutation carriers harbouring additional rare variants in CARD 14 or AP 1S3 indicates a more complex mode of inheritance of pustular psoriasis. Our results suggest that, in heterozygous IL36RN mutation carriers, there are additional disease‐causing genetic factors outside IL 36 RN .