Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: OSMR

Green List (high evidence)

Comment on list classification: There are 8 unrelated patients reported in literature with biallelic OSMR variants and syndromic atopic dermatitis with peripheral eosinophilia and markedly elevated serum IgE. Hence, this gene can be promoted to Green at the next GMS update.

Created: 29 Jul 2026, 2:08 p.m. | Last Modified: 29 Jul 2026, 2:08 p.m.

Panel Version: 9.31

PMID: 41783139 Andersen et al., 2026
Study described a patient (57-year-old man of Caucasian Danish descent) presenting with elevated IgE levels, atopic eczema, chronic pulmonary aspergillosis, frequent secondary staphylococcal skin infections and pustules, and bone fractures. Blood profiling showed elevated IgE-expressing plasmablasts and peripheral T follicular helper cells and atypical memory B cells. WGS showed that P1 was homozygous for a missense variant c.1307T>A, p.Val436Asp.
A significant reduction in OSMR surface expression on patient dermal fibroblasts compared to controls was found by flow cytometry. A skin biopsy showed perivascular inflammation with lymphocytes and eosinophils but no amyloid deposits.

PMID: 42221229 Samra et al., 2026
Study identified 10 patients from 7 unrelated kindreds spanning Europe, South Asia, and the Arab world carrying complete biallelic loss-of-function OSMR variants, causing a distinct recessive primary atopic disorder rather than dominant amyloidosis. 4/7 families were consanguineous. Patients presented with early-onset, severe, widespread atopic dermatitis with peripheral eosinophilia and markedly elevated serum IgE.
OSMR variants detected were a mix of missense, stop-gain, and frameshift. Heterozygous parents were unaffected.
In 3 pedigrees (A, B, & C), the OSMR: c.1307T>A, p.Val436Asp variant was reported. It has MAF = 0.004260 in the European population, and 14 total homozygotes reported in gnomAD v4.1.1. However, available UKB clinical data for 9 of these p.Val436Asp homozygous individuals suggest enrichment of allergic disease or cutaneous features, including elevated peripheral eosinophil counts or percentages (3/9) and documented allergic or dermatologic diagnoses in several individuals. Other reported variants not present in gnomAD v4.

OSMR is associated with AD Amyloidosis, primary localized cutaneous, 1, OMIM:105250; no recessive association added in OMIM, G2P, or ClinGen (accessed 29th July 2026).

Created: 29 Jul 2026, 11:52 a.m. | Last Modified: 29 Jul 2026, 2:03 p.m.

Panel Version: 9.30

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
atopic eczema, MONDO:0004980

Publications

• 41783139
• 42221229

Green List (high evidence)

Samra et al. identified 10 affected individuals from seven unrelated families with germline biallelic loss-of-function variants in OSMR who shared a phenotype of early-onset, severe, widespread atopic dermatitis with peripheral eosinophilia and markedly elevated serum IgE. All patient-derived OSMRβ variants failed to localize to the cell surface, resulting in selective loss of OSM-dependent signaling. Patient cells showed markedly reduced OSM-induced phosphorylation of STAT1, STAT3, and STAT5, while signaling through other IL-6 family receptor complexes remained intact. Transcriptomic profiling of patient primary dermal fibroblasts revealed consistent downstream effects, including loss of interferon-responsive and inflammatory gene programs. Re-expression of wild-type OSMR restored receptor surface expression, STAT activation, and transcriptional responses, confirming a causal loss-of-function mechanism. Together, these findings establish biallelic OSMR deficiency as a novel primary atopic disorder.
Sources: Literature

Created: 17 Jun 2026, 2:02 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Atopic dermatitis; eosinophilia; elevated IgE

Publications

• 42221229