K.-P. Peters, S. Kõks, H. Ständer, K. Reich, S. Löhr, A. Jacobi, K. G. Griewank, R. Renner, S. Philipp, T. Schill, A. Weyergraf, D. Wilsmann-Theis, H. Sticht, K. Steinz, J. Christoph -Prinz, L. Vogelsang, K. Schäkel, R. Mössner, P. Gkogkolou, S. Uebe, L. Ebertsch, K. Kingo, P. Schulz, U. Hüffmeier, A. Körber, M. Müller, V. Oji, S. Frey, M. Sticherling, S. Gerdes
Background
Rare variants in the genes IL36RN, CARD14 and AP1S3 have been identified to cause/ 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, 2 with acute generalized exanthematous pustulosis and 4 with acrodermatitis continua suppurativa Hallopeau. We screened IL36RN and AP1S3 for intragenic copy-number-variants, 258 PPP patients for coding changes in AP1S3. 11 heterozygous IL36RN mutations carriers were analyzed for a 2nd non-coding IL36RN mutation. Genotype-phenotype-correlations in carriers/ non-carriers 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. Bi-allelic and mono-allelic IL36RN mutations were identified in 15 and 5 GPP patients, respectively. Non-coding rare IL36RN variants were not identified in heterozygous carriers. The only significant genotype-phenotype-correlation observed for IL36RN mutation carriers was early age of disease onset. Additional rare CARD14 or AP1S3 variants were identified in 15% of IL36RN mutations carriers.
Conclusions
The identification of IL36RN mutation carriers harboring additional rare variants in CARD14 or AP1S3, indicates a more complex mode of inheritance of pustular psoriasis. Our results suggest additional disease-causing genetic factors in heterozygous IL36RN mutation carriers outside IL36RN.
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