Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: LY96

Red List (low evidence)

Comment on list classification: There is only one family and functional evidence available in support of the disease association. The phenotype is variable across the two siblings from the same family. Hence, this gene can only be rated red with the current evidence.

Created: 6 Aug 2026, 3:41 p.m. | Last Modified: 6 Aug 2026, 3:46 p.m.

Panel Version: 9.75

PMID:36462957 (2022) reported a homozygous in-frame deletion in the LY96 gene (c.347_349delCAA; p.Thr116del) identified via whole-exome sequencing in a patient with very early onset inflammatory bowel disease and a sibling presenting with pneumonia and otitis media. LY96 gene encodes myeloid differentiation protein 2 (MD2).

iPSC-derived macrophages lacking MD2 or carrying the Thr116del variant showed impaired NF-κB/MAPK signaling and TLR4 endocytosis. In addition, MD2-deficient macrophages showed decreased cytokine expression (IL-6, TNF, IL-10) in response to LPS/gram-negative bacteria - confirming a gram-negative-specific TLR4 signaling defect.

This gene has not yet been associated with relevant phenotypes either in OMIM or in ClinGen (last accessed 06 August 2026).

Created: 6 Aug 2026, 3:38 p.m. | Last Modified: 6 Aug 2026, 3:38 p.m.

Panel Version: 9.73

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
inflammatory bowel disease, MONDO:0005265; pneumonia, MONDO:0005249; otitis media, MONDO:0005441

Publications

• 36462957

Red List (low evidence)

Li et al. described 2 patients from 1 kindred, harboring a homozygous mutation in the LY96 gene (c.347_349delCAA). They presented with very early-onset inflammatory bowel disease, recurrent pneumonia, and otitis media. The underlying mechanism and phenotype were validated in vitro using genetically engineered induced pluripotent stem cell (iPSC)-derived macrophages. Both LY96 knockout models and the specific patient mutation knock-in models successfully recreated the immunodeficiency phenotype, demonstrating impaired activation of NF-κB and MAPK signaling, defective TLR4 endocytosis, and significantly decreased cytokine expression (e.g., IL-6, TNF, IL-10) upon challenge with lipopolysaccharide (LPS) and Gram-negative bacteria, while host defense responses to Gram-positive bacteria remained intact.
Sources: Expert list, Literature

Created: 17 Jun 2026, 4:25 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Inflammatory bowel disease; Pneumonia; Otitis media; Abnormal inflammatory response; Recurrent bacterial infections

Publications

• 36462957