Background Singleton-Merten syndrome (SGMRT) is a rare immunogenetic disorder that variably features juvenile open-angle glaucoma (JOAG), psoriasiform skin rash, aortic calcifications and skeletal and dental dysplasia. Few families have been described and the genotypic and phenotypic spectrum is poorly defined, with variants in DDX58 (DExD/H-box helicase 58) being one of two identified causes, classified as SGMRT2.
Methods Families underwent deep systemic phenotyping and exome sequencing. Functional characterisation with in vitro luciferase assays and in vivo interferon signature using bulk and single cell RNA sequencing was performed.
Results We have identified a novel DDX58 variant c.1529A>T p.(Glu510Val) that segregates with disease in two families with SGMRT2. Patients in these families have widely variable phenotypic features and different ethnic background, with some being severely affected by systemic features and others solely with glaucoma. JOAG was present in all individuals affected with the syndrome. Furthermore, detailed evaluation of skin rash in one patient revealed sparse inflammatory infiltrates in a unique distribution. Functional analysis showed that the DDX58 variant is a dominant gain-of-function activator of interferon pathways in the absence of exogenous RNA ligands. Single cell RNA sequencing of patient lesional skin revealed a cellular activation of interferon-stimulated gene expression in keratinocytes and fibroblasts but not in neighbouring healthy skin.
Conclusions These results expand the genotypic spectrum of DDX58-associated disease, provide the first detailed description of ocular and dermatological phenotypes, expand our understanding of the molecular pathogenesis of this condition and provide a platform for testing response to therapy.
- autoimmune diseases
- and neonatal diseases and abnormalities
- eye diseases
- gain of function mutation
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Contributors Conceptualisation and study design: LP, BLB, JEG, LCT, RBH. Acquisition, analysis and interpretation of data: all authors. Initial drafting of manuscript: LP. Revision and review of manuscript: all authors. Final approval of the submitted manuscript: all authors. Obtained funding: LP, JEG, LCT, JMK, JER, SH, RBH, BPB. Study supervision: LP, JEG, LCT, SH, RBH, RTG-M, BPB, JER.
Funding The NEI K12 EY022299 (LP) and NEI P30 EY07003 (LP). NEI intramural funds (RBH, BG, BPB). The National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health R01-AR060802 (JEG), P30-AR075043 (JEG) and K01-AR072129 (LCT) and the National Institute of Allergy and Infectious Diseases under R01-AR069071 (JEG), the A. Alfred Taubman Medical Research Institute (JEG. and JMK) and the Parfet Emerging Scholar Award (JMK), the Roche Postdoctoral Fellowship (HW).
Competing interests None declared.
Patient consent for publication Patient consent or next of kin consent obtained.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available on reasonable request. All underlying data including genomic, single cell RNA sequencing data and deidentified clinical data and are available on reasonable request from the corresponding author or the study team.
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