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

## TL;DR

A new genetic variant in DSG1 is linked to a mild skin condition in a family, showing how gene function can affect disease severity.

## Contribution

The first report of a homozygous DSG1 splice-site variant causing mild, non-syndromic PPK.

## Key findings

- A homozygous DSG1 splice-site variant c.685-3T>A was identified in Pakistani siblings with mild PPK.
- Partial retention of wild-type DSG1 transcripts may explain the mild clinical phenotype.
- The study shows phenotypic variability in DSG1-related disorders based on residual gene activity.

## Abstract

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.