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Abstract
Purpose
Singleton-Merten syndrome manifests as dental dysplasia, glaucoma, psoriasis, aortic calcification, and skeletal abnormalities including tendon rupture and arthropathy. Pathogenic variants in IFIH1 have previously been associated with the classic Singleton-Merten syndrome, while variants in DDX58 has been described in association with a milder phenotype, which is suggested to have a better prognosis. We studied a family with severe, “classic” Singleton-Merten syndrome.
Methods
We undertook clinical phenotyping, next-generation sequencing, and functional studies of type I interferon production in patient whole blood and assessed the type I interferon promoter activity in HEK293 cells transfected with wild-type or mutant DDX58 stimulated with Poly I:C.
Results
We demonstrate a DDX58 autosomal dominant gain-of-function mutation, with constitutive upregulation of type I interferon.
Conclusions
DDX58 mutations may be associated with the classic features of Singleton-Merten syndrome including dental dysplasia, tendon rupture, and severe cardiac sequela.
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Details
1 Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
2 Institute of Genetics and Molecular Medicine, Centre for Genomic and Experimental Medicine, The University of Edinburgh, Edinburgh, UK; Laboratory of Neurogenetics and Neuroinflammation, Paris Descartes University, Sorbonne-Paris-Cité, Institut Imagine, Paris, France
3 Office of the Clinical Director and Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
4 Office of the Clinical Director, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
5 Translational Autoinflammatory Disease Studies (TADS), National Institute of Allergy and Infectious Diseases (NIAID) National Institutes of Health, Bethesda, MD, USA
6 Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, USA
7 Biology Department in Morrissey College of Arts and Sciences, Boston College, Chestnut Hill, USA
8 Manchester Centre for Genomic Medicine, St Mary’s Hospital, Manchester University Hospitals NHS Foundation Trust Manchester Academic Health Sciences Centre, Manchester, UK; Division of Evolution and Genomic Sciences, School of Biological Sciences, University of Manchester, Manchester, UK