DDX58 and Classic Singleton-Merten Syndrome.

Area of Science:

• Genetics
• Immunology
• Rare Diseases

Background:

• Singleton-Merten syndrome (SMS) is a rare genetic disorder characterized by dental dysplasia, glaucoma, psoriasis, aortic calcification, and skeletal abnormalities.
• Pathogenic variants in IFIH1 are linked to classic SMS, while DDX58 variants are associated with a milder phenotype.

Observation:

• This study investigated a family with severe, classic Singleton-Merten syndrome.
• Clinical phenotyping, next-generation sequencing, and functional studies were performed.
• Type I interferon production and promoter activity were assessed in patient samples and cell lines.

Findings:

• A DDX58 autosomal dominant gain-of-function mutation was identified.
• This mutation leads to constitutive upregulation of type I interferon.
• The identified mutation is associated with the classic features of Singleton-Merten syndrome.

Implications:

• DDX58 mutations are implicated in the pathogenesis of classic Singleton-Merten syndrome.
• Findings suggest a role for DDX58 in the severe manifestations of SMS, including dental dysplasia, tendon rupture, and cardiac sequelae.
• This research expands the understanding of genotype-phenotype correlations in Singleton-Merten syndrome and highlights the importance of DDX58 in interferon regulation.