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Desmoplakin (DSP) is a key desmosomal cytolinker critical for anchoring keratin intermediate filaments to the intercellular junctions in epidermis and myocardium. Recessive truncating variants in DSP cause lethal acantholytic epidermolysis bullosa (LAEB), a severe form of suprabasal epidermolysis bullosa simplex characterized by extensive skin and mucosal fragility with transcutaneous fluid loss, total alopecia, natal teeth, and anonychia.
Two clinical reports document biallelic DSP variants in three affected neonates. A single isolated case carried compound DSP truncations with absent tail‐domain expression (PMID:19945626). A consanguineous family presented two siblings homozygous for a deletion predicted to truncate both rod and C‐terminal domains, confirming autosomal recessive inheritance with 2 affected siblings (PMID:20302578).
The recurrent homozygous deletion c.2875_2880del (p.Lys959MetfsTer5) was identified in the second report; this variant disrupts the exon 20 donor splice site, resulting in loss of the DSP rod domain and C‐terminus, and was absent in healthy relatives (PMID:20302578).
Histopathology and ultrastructural studies reveal suprabasal clefting with acantholysis, abnormal desmosomes lacking the inner dense plaque, and disconnection of keratin filaments—consistent with DSP loss of function (PMID:19945626). Immunoblotting in the isolated case confirmed truncated DSP polypeptides missing the tail domain required for keratin binding.
The genetic and experimental data together support a Moderate ClinGen clinical validity classification: 3 probands in 2 families, autosomal recessive segregation, and concordant functional disruption of desmosome structure.
Key Take-Home: Biallelic truncating DSP mutations lead to LAEB through failure of keratin‐desmosome linkage, providing a clear molecular diagnosis for early neonatal presentation and guiding genetic counseling and potential future therapies.
Gene–Disease AssociationModerate3 probands (one isolated case, two siblings), autosomal recessive segregation, concordant ultrastructural and protein data Genetic EvidenceModerateBiallelic truncating DSP variants in three affected neonates across two families Functional EvidenceModerateUltrastructural studies show desmosome disruption; truncated DSP lacking keratin‐binding tail confirmed |