Clinical and genetic characterization of Netherton syndrome due to SPINK5 founder variant in Latvian population

Abstract Objective Netherton syndrome (NS) (OMIM:256500) is a very rare autosomal recessive multisystem disorder mostly affecting ectodermal derivatives (skin and hair) and immune system. It is caused by biallelic loss‐of‐function variants in the SPINK5 gene, encoding the protease inhibitor lymphoepithelial Kazal‐type‐related inhibitor (LEKTI). Material, Methods and Results Here, we describe NS clinical and genetic features of homogenous patient group: 9 individuals from 7 families with similar ethnic background and who have the same SPINK5 variant (NM_006846.4: c.1048C > T, p.(Arg350*)) in homozygous or compound heterozygous states, suggesting that it is a common founder variant in Latvian population. Indeed, we were able to show that the variant is common in general Latvian population, and it shares the same haplotype among the NS individual. It is estimated that the variant arose >1000 years ago. Clinically, all nine patients exhibited typical NS skin changes (scaly erythroderma, ichthyosis linearis circumflexa , itchy skin), except for one patient who has a different skin manifestation—epidermodysplasia. Additionally, we show that developmental delay, previously underrecognized in NS, is a common feature among these patients. Conclusions This study shows that the phenotype of NS individuals with the same genotype is highly homogeneous.