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

Area of Science:

• Genetics
• Dermatology
• Molecular Biology

Background:

• Hereditary palmoplantar keratoderma (PPK) is a group of palmoplantar epidermal differentiation disorders (pEDDs).
• Desmoglein 1 (DSG1) variants are known causes of PPK, with monoallelic variants typically causing non-syndromic PPK and biallelic variants causing syndromic PPK (SAM syndrome).

Purpose of the Study:

• To report the first case of a homozygous DSG1 variant associated with mild, non-syndromic PPK.
• To investigate the molecular mechanism and phenotypic variability of DSG1-related pEDDs.

Main Methods:

• Exome sequencing was performed on affected siblings.
• Familial cosegregation analysis was conducted.
• In silico analyses and an exon-trap assay were used to assess the effect of the identified variant on DSG1 splicing.

Main Results:

• A homozygous splice-site variant (c.685-3T>A) in the DSG1 gene was identified in Pakistani siblings with mild, non-syndromic striate PPK.
• The variant disrupted DSG1 splicing, but some wild-type transcripts were retained.
• In silico analyses suggested a low probability of complete exon skipping.

Conclusions:

• This study reports the first instance of a homozygous DSG1 variant causing mild, non-syndromic PPK.
• The findings underscore the phenotypic variability within DSG1-related disorders, potentially linked to residual DSG1 activity.
• This expands the understanding of genotype-phenotype correlations in DSG1-pEDDs.