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Singleton-Merten syndrome 1 (SMS1) is a rare autosomal dominant type I interferonopathy characterized by early and extreme arterial and valvular calcification, dental anomalies including periodontitis and root resorption, osteoporosis, acro-osteolysis of the phalanges, and musculoskeletal weakness. SMS1 arises from gain-of-function mutations in the IFIH1 gene encoding the cytosolic sensor MDA5, leading to constitutive activation of type I interferon signaling. Affected individuals present in early childhood with developmental delay, progressive motor weakness (HP:0001324), osteopenia progressing to osteoporosis (HP:0000939), and osteolytic defects of the phalanges (HP:0009771). Genetic diagnosis is confirmed by identifying heterozygous pathogenic variants in IFIH1.
Initial exome sequencing identified a recurrent heterozygous missense variant, c.2465G>A (p.Arg822Gln), in four affected subjects from two multiplex families and a simplex case, establishing a de novo and segregating gain-of-function mechanism (PMID:25620204). The inheritance is autosomal dominant with both inherited and de novo occurrences. Segregation analysis demonstrated co-segregation of c.2465G>A with disease in at least two generations in multiplex kindreds. No loss-of-function variants have been associated with SMS1, underscoring a specific gain-of-function pathogenic mechanism.
Functional studies of the p.Arg822Gln variant revealed enhanced MDA5 signaling in vitro, with increased interferon-β induction and upregulation of interferon-stimulated genes in patient blood cells (PMID:25620204). Constitutive type I interferon signature in patient leukocytes confirmed pathway overactivation. In a landmark therapeutic trial, off-label use of the JAK1/2 inhibitor ruxolitinib rapidly normalized the interferon signature and resolved psoriatic skin lesions in a nine-year-old patient, with sustained improvement in muscle strength and bone density (PMID:35410415). Rescue of hyperinflammation by targeted JAK inhibition supports the pathogenic role of IFIH1 gain-of-function.
There are no reported studies disputing the association between IFIH1 variants and SMS1. All reported pathogenic alleles cluster near the ATP‐binding region of MDA5 and exhibit enhanced RNA binding or decreased ATP hydrolysis and filament disassembly. Experimental concordance across biochemical assays, patient cell signatures, and clinical response to targeted therapy provides robust mechanistic validation. Additional rare IFIH1 variants have been identified in related type I interferonopathies but not in SMS1, indicating phenotypic specificity of the p.Arg822Gln allele.
In aggregate, the genetic and experimental data fulfill ClinGen criteria for a Strong gene–disease association. The predominance of a recurrent gain-of-function variant, multi-family segregation, and concordant functional and therapeutic rescue experiments underpin clinical validity. Genetic testing for IFIH1 variants is critical for early diagnosis, informs prognosis, and enables personalized treatment with JAK inhibitors. Key take-home: IFIH1 gain-of-function mutations cause SMS1 and predict responsiveness to JAK inhibition.
Gene–Disease AssociationStrongFive unrelated probands including a simplex case and two multiplex families; de novo and segregating gain-of-function c.2465G>A variant; concordant functional data Genetic EvidenceStrongRecurrent c.2465G>A variant in four subjects from two families and a simplex case; autosomal dominant inheritance with segregation across generations Functional EvidenceModerateIn vitro assays demonstrate enhanced interferon-β induction by p.Arg822Gln; patient cells show chronic IFN signature and respond to ruxolitinib |