Classifying novel DSG1 variants on disease severity in SAM syndrome and palmoplantar keratoderma

Background: Biallelic pathogenic variants in DSG1 encoding desmoglein 1 cause severe atopic dermatitis, multiple allergies, and metabolic wasting (SAM) syndrome, whereas heterozygous variants result in palmoplantar keratoderma (PPK). Objectives: Here we investigate genetic variants, pathophysiology and clinical findings of three patients with SAM syndrome and eleven patients diagnosed with PPK. Methods: Genetic analysis was used to identify variants in DSG1. Immunofluorescence staining was performed to determine DSG1 protein expression in SAM patients. Results: In SAM syndrome and PPK patients eleven novel variants in DSG1 were identified. In the SAM patients with a severe, intermediate and mild phenotype, we identified compound heterozygous, a known dominant, and homozygous variants, respectively, while clinical variability in PPK patients was observed. The variants in DSG1 for SAM and PPK included scarcely reported missense (n = 4), nonsense (n = 4), splice-site (n = 2) variants, a small deletion/duplication (n = 3) and a never reported gross deletion (n = 1). Immunofluorescence staining in skin of SAM patients showed that the severity of the symptoms correlates with total or partial extracellular absence of DSG1, suggesting a potential difference in protein stability. Hence, loss-of-function variants that occur in the extracellular or transmembrane domains of DSG1, resulted in loss of intercellular connecting and anchoring capability, while intracellular variants, partly preserve the adhesive function of DSG1. Conclusion: Our results contribute to better understanding the genotype-phenotype correlation associated with DSG1 variants, although the exact pathophysiological mechanisms remain to be elucidated.