DDX58 and Classic Singleton-Merten Syndrome.

Carlos R Ferreira, Yanick J Crow, William A Gahl, Pamela J Gardner, Raphaela Goldbach-Mansky, Sun Hur, Adriana Almeida de Jesús, Michele Nehrebecky, Ji Woo Park, Tracy A Briggs

Journal: Journal of clinical immunology 2019;39(1):75-80

PMID: 30574673

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.

Address: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. [email protected].; 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.; Office of the Clinical Director and Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.; Office of the Clinical Director, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.; Translational Autoinflammatory Disease Studies (TADS), National Institute of Allergy and Infectious Diseases (NIAID) National Institutes of Health, Bethesda, MD, USA.; Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, USA.; Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.; Biology Department in Morrissey College of Arts and Sciences, Boston College, Chestnut Hill, USA.; Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University Hospitals NHS Foundation Trust Manchester Academic Health Sciences Centre, Manchester, UK. [email protected].; Division of Evolution and Genomic Sciences, School of Biological Sciences, University of Manchester, Manchester, UK. [email protected].
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