Autoinflammatory disorders

Gene: SHARPIN

Green List (high evidence)

Comment on list classification: There are two unrelated patients and functional evidence including mouse model available in support of the association of SHARPIN gene with autoinflammatory disease. Hence, this gene can be promoted to green rating in the next GMS update.

Created: 6 Aug 2026, 7:19 p.m. | Last Modified: 6 Aug 2026, 7:19 p.m.

Panel Version: 9.78

PMID:38609546 (2024) reported two unrelated patients with homozygous SHARPIN loss-of-function frameshift variants (c.220dupC/ p.Leu74ProfsX86 in P1 and c.613_614delCT/ p.Leu205GlufsX21 in P2) causing a novel autosomal recessive autoinflammatory/immunodeficiency syndrome termed "sharpenia".

The patients presented with:
P1: Recurrent fever, parotitis, sterile joint inflammation/arthritis (ankle), colitis, chronic otitis media requiring tympanoplasty
P2: Recurrent fever with lymphadenopathy and vomiting; elevated CRP; later episode with altered mental status treated as suspected multisystem inflammatory syndrome in children (MIS-C).

Extensive functional work on patient 1 showed that the mutant protein is absent, linear ubiquitin assembly complex (LUBAC) is destabilized, NF-κB signaling is impaired, and TNF-induced apoptosis is enhanced, whereas this was not verified in Patient 2 due to death. Anti-TNF treatment in P1 produced complete clinical and trascriptional resolution of autoinflammation.

PMID:17538631 (2007) demonstrated that two independently arising spontaneous mutations in the mouse Sharpin gene, cpdm and cpdm(Dem), cause a chronic proliferative dermatitis phenotype, which is characterized histologically by severe inflammation, eosinophilic dermatitis and defects in secondary lymphoid organ development. However, the human disease did not recapitulate the severe dermatological phenotype observed in Sharpin-deficient mice.

This gene has been associated with relevant phenotype in OMIM (MIM #620795, last accessed 06 August 2026), but not yet in ClinGen.

Created: 6 Aug 2026, 7:17 p.m. | Last Modified: 6 Aug 2026, 7:17 p.m.

Panel Version: 9.75

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Autoinflammation with episodic fever and immune dysregulation, OMIM:620795; autoinflammation with episodic fever and immune dysregulation, MONDO:0968982

Publications

• 17538631
• 38609546

Oda et al. described 1 patient from 1 kindred, harboring biallelic loss-of-function mutations in the SHARPIN gene. They presented with distinct clinical autoinflammatory features, recurrent fevers, and subtle immunodeficiency. The underlying mechanism was validated ex vivo using patient-derived cells, demonstrating that the absence of SHARPIN severely destabilizes the linear ubiquitin chain assembly complex (LUBAC), resulting in impaired NF-κB signaling, defective linear ubiquitination, and dysregulated TNF-mediated cell death. The phenotype and mechanism were further validated using in vivo animal models; complete knockout Sharpin-deficient mice (Sharpin cpdm) successfully recreated the severe chronic proliferative dermatitis and multi-organ autoinflammation, confirming the gene's critical role in maintaining immune homeostasis and preventing aberrant cell death.
Sources: Literature, Expert list

Created: 17 Jun 2026, 4:28 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Autoinflammation; Immunodeficiency; Recurrent fever; Dermatitis; Recurrent infections

Publications

• 38609546