STING1 – Familial Chilblain Lupus

Familial chilblain lupus is an autosomal dominant monogenic cutaneous lupus characterized by cold‐induced acral chilblains and vasculitic skin lesions. In a single five‐member kindred, a heterozygous gain‐of‐function variant in STING1 segregated with disease in all affected individuals, supporting causality (PMID:27566796).

Clinical Validity (Moderate)

A single multigenerational family with five affected members demonstrated co‐segregation of a STING1 variant with chilblain lupus. Although limited to one pedigree, the complete penetrance across generations and concordant clinical phenotype warrant a ClinGen “Moderate” classification (five probands; one family segregation; functional concordance) (PMID:27566796).

Genetic Evidence (Moderate)

Inheritance is autosomal dominant. Five affected relatives across three generations exhibited consistent chilblain lupus features. Exome sequencing identified a private heterozygous STING1 coding change that was absent in unaffected family members. The variant co‐segregated perfectly with disease status (affected_relatives=4) and was novel in population databases, supporting a moderate level of genetic evidence.

Functional Evidence (Moderate)

Structural homology modelling predicted destabilization of the autoinhibitory STING dimer interface. In vitro assays of cells transfected with mutant STING1 demonstrated ligand‐independent homodimerization, constitutive activation of an IFN-β reporter, and elevated expression of interferon-stimulated genes by Western blotting and RT-PCR, consistent with a gain-of-function mechanism.

Conflicting Evidence

No studies to date have refuted the association of STING1 gain-of-function variants with familial chilblain lupus.

Integrated Interpretation

Heterozygous gain-of-function variants in STING1 cause autosomal dominant familial chilblain lupus through constitutive activation of type I interferon signaling. The combination of perfect segregation in a multigenerational pedigree and robust functional validation supports a moderate clinical validity classification. Further independent pedigrees and functional rescue studies would strengthen the evidence to a definitive level. Key take-home: STING1 sequencing should be considered in patients with familial cold-induced chilblains to guide targeted interferon-modulating therapies.

References

• Annals of the rheumatic diseases • 2017 • Familial chilblain lupus due to a gain-of-function mutation in STING PMID:27566796

Evidence Based Scoring (AI generated)