IFIH1 – Singleton-Merten Dysplasia

Singleton-Merten dysplasia (SMS) is an autosomal dominant interferonopathy marked by early-onset periodontitis, root resorption, osteopenia (HP:0000938), osteoporosis (HP:0000939), and vascular calcification. A landmark exome study identified a recurrent heterozygous missense variant, c.2465G>A (p.Arg822Gln), in IFIH1 in four SMS subjects from two families and a simplex case (PMID:25620204). Subsequent reports confirmed the same variant in a mother–daughter pair, expanding the phenotype to include systemic lupus erythematosus and neuroinflammatory features (PMID:28319323; PMID:28475458).

1 Assess Clinical Validity

• ClinGen classification: Strong.
• Rationale: c.2465G>A (p.Arg822Gln) observed in 6 probands across 4 families; segregation in a mother–daughter pair; concordant gain-of-function functional data.

2 Genetic Evidence

• Inheritance mode: autosomal dominant.
• Segregation: 2 additional affected relatives with co-segregating variant.
• Case series & variant spectrum: 6 SMS probands carrying the recurrent missense variant c.2465G>A (p.Arg822Gln).
• No loss-of-function or deep-intronic variants reported for SMS.

3 Functional / Experimental Evidence

• Mechanism: gain-of-function of MDA5 leading to constitutive type I interferon induction.
• Key assays: increased interferon-β induction in vitro; upregulation of interferon-stimulated genes in patient blood and dental cells; rescue of joint deformities and interferon signature reduction with baricitinib in overlapping cases.

4 Conflicting Evidence

• No studies to date have refuted the IFIH1–SMS association; variable expressivity and additional phenotypes reflect interferonopathy spectrum rather than locus heterogeneity.

5 Integration & Clinical Utility

Genetic and functional data firmly establish IFIH1 c.2465G>A (p.Arg822Gln) as a causative gain-of-function variant for Singleton-Merten dysplasia. This provides a diagnostic marker for SMS, informs family counseling, and supports therapeutic targeting of type I interferon signaling. Key take-home: Screening IFIH1 for c.2465G>A enables precise SMS diagnosis and guides interferon-modulating treatment.

References

• American Journal of Human Genetics • 2015 • A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome PMID:25620204
• American Journal of Medical Genetics Part A • 2017 • Further evidence for specific IFIH1 mutation as a cause of Singleton-Merten syndrome with phenotypic heterogeneity PMID:28319323
• Journal of Interferon & Cytokine Research • 2017 • MDA5-Associated Neuroinflammation and the Singleton-Merten Syndrome: Two Faces of the Same Type I Interferonopathy Spectrum PMID:28475458

Evidence Based Scoring (AI generated)