This study is the first in the field of psoriasis demonstrating a strong association between genetic markers and positive response to drug treatment. Validation of this result in larger studies, as well as analysis of other drug treatments, could provide the basis for individually tailored treatment, along with increased cost effectiveness and reduced unnecessary exposure to toxicity.

Netherton syndrome (OMIM #256500) is a rare but severe autosomal recessive form of ichthyosis that affects the skin, hair, and immune system. The identification of SPINK5, which encodes for the serine protease inhibitor LEKTI, as the gene responsible for Netherton syndrome, enabled the search for causative mutations in Netherton syndrome patients and families. However, information regarding these mutations and their association with the pathological Netherton syndrome phenotype is scarce. Herein, we provide an up-to-date overview of 80 different mutations in exonic as well as intronic regions that have been currently identified in 172 homozygous or compound heterozygous patients from 144 families. Genotypes with mutations located more upstream in LEKTI correlate with more severe phenotypes compared with similar mutations located towards the 3' region. Furthermore, splicing mutations and post-transcriptional mechanism of nonsense-mediated mRNA decay affect LEKTI expression in variable ways. Genotype-phenotype correlations form the basis of prenatal diagnosis in families with a history of Netherton syndrome and when consanguinity is implied.

This study was supported by Principia Biopharma Inc., a Sanofi company. Conflicts of interestConflicts of interest statements can be found in the Appendix. Data availabilityQualified researchers may request access to patientlevel data and related documents (including, e.g., the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications). Patientlevel data will be anonymized, and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at https://www. clinicalstudydatarequest.com.