DSP – Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis

De novo heterozygous missense variants in the spectrin repeat domain of the desmoplakin gene (DSP) have been implicated in a novel cardio-cutaneous syndrome characterized by early-onset erythrokeratodermia, progressive dilated cardiomyopathy, woolly hair, keratoderma and tooth agenesis. Five unrelated probands each carried a distinct de novo DSP missense change clustering within a single spectrin repeat (5 probands; [PMID:26604139]) with consistent histopathological and clinical findings. Inheritance is autosomal dominant with no observed transmission to additional relatives. A representative variant is c.2552T>A (p.Leu851Gln), which disrupts desmoplakin–intermediate filament interactions.

Functional studies in patient skin and cardiac tissues demonstrate mislocalization of desmosomal components and connexin-43, desmosome aggregation, widened intercellular spaces and lipid secretory defects, consistent with impaired intercellular adhesion in both epidermis and myocardium ([PMID:26604139]). These cellular phenotypes support a dominant negative mechanism in which mutant desmoplakin compromises desmosome assembly and stability. Although elegant functional data confirm pathogenicity, evidence is limited to a single cohort without extended segregation, resulting in a Limited clinical validity classification.

Key Take-home: DSP missense variants in the spectrin repeat domain cause a distinct autosomal dominant cardio-cutaneous syndrome, and genetic testing may guide diagnosis and management.

References

• Human molecular genetics • 2016 • Dominant de novo DSP mutations cause erythrokeratodermia-cardiomyopathy syndrome. PMID:26604139

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