Bi-Allelic DSG1 Splice-Site Variant Identified in a Family With Non-Syndromic Striate Palmoplantar Keratoderma

Hereditary palmoplantar keratoderma (PPK) involves hyperkeratosis of the palmoplantar skin and belongs to the palmoplantar epidermal differentiation disorders (pEDDs). One causal gene is Desmoglein 1 (DSG1), which encodes a protein crucial for epidermal integrity. Monoallelic DSG1 variants cause mild, non-syndromic PPK, whereas bi-allelic DSG1 variants typically cause syndromic PPK with severe additional clinical features (SAM syndrome). Here, we report the first detection of a homozygous DSG1 variant in mild, non-syndromic PPK. Pakistani siblings presented with striate PPK, characterized by deep palmar creases and plantar fissures only. Exome sequencing revealed the homozygous DSG1 splice-site variant c.685-3T>A with familial cosegregation. In silico analyses indicated a low probability of exon 7 skipping. An exon-trap assay confirmed splicing disruption, although some wild-type (WT) transcripts were also detected. The partial retention of DSG1 WT transcripts may explain the mild phenotype. This finding highlights the phenotypic variability of DSG1-related disorders (DSG1-pEDD), related to residual DSG1 activity.