Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: GPR15

Green List (high evidence)

Comment on list classification: There are four unrelated families reported with GPR15 variants and with early-onset inflammatory bowel disease. Patients were reported with both biallelic and monoallelic inheritance in at least two families each - biallelic in families 1-3 and monoallelic carriers in families 2 and 4. However, the phenotype is milder in monoallelic carriers. There is also functional evidence available from both homozygous and heterozygous varaiants and from GPR15 knockout model.

Hence, this gene should be promoted to green rating with 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal' MOI in the next GMS update.

Created: 8 Aug 2026, 9:49 a.m. | Last Modified: 8 Aug 2026, 9:49 a.m.

Panel Version: 9.89

PMID:42259915 (2026) reported multiple patients from four different kindreds with early-onset inflammatory bowel disease (IBD) associated with GPR15 loss-of-function variants, identified via genetic sequencing of affected paediatric IBD families, with causality supported by patient T-cell functional assays and a Gpr15-knockout mouse colitis model.

Biallelic inheritance: Three probands carried biallelic loss-of-function variants — compound heterozygous p.Asp306Asn/p.Gln281Ter in first family (includes asymptomatic sister of proband with same compound heterozygous variants), homozygous p.Tyr215Ter in second family (includes monoallelic carriers) and doubly homozygous p.Tyr132Ser and p.Phe159Ile missense variants in third family. The p.Phe159Ile variant is predictdd to be benign. The p.Tyr132Ser variant is present in gnomAD databases at a non-negligible frequency (MAF = 0.0012, 1,916 heterozygotes and 20 homozygotes in v.4.1.1), including homozygous people, suggesting a hypomorphic allele with incomplete penetrance. Biallelic variants are associated with a more severe early-onset IBD phenotype, with partial penetrance among biallelic carriers (3/4, 75%).

Functional assays performed on biallelic patient T cells demonstrated reduced GPR15 cell-surface expression, impaired Ca²⁺ signaling, and defective chemotaxis, with all defects rescued by re-expression of wild-type GPR15; Gpr15-null mice recapitulated spontaneous colitis, providing in vivo evidence for complete loss of function.

Monoallelic inheritance: Two families carried heterozygous truncating variants — p.Gln281Ter in one family (fourth family) and p.Tyr215Ter in another (monoallelic carriers in second family)— segregating with early-onset IBD in a dominant pattern but with incomplete penetrance (4/10 carriers affected, 40%); some carriers were only mildly affected. The same functional studies in patient-derived T cells demonstrated reduced GPR15 surface expression, impaired Ca²⁺ signaling, and defective chemotaxis for both heterozygous variants, again rescued by wild-type GPR15, directly linking the monoallelic genotype to the cellular phenotype.

This gene has not yet been associated with relevant phenotypes either in OMIM or in ClinGen (last accessed 08 August 2026).

Created: 8 Aug 2026, 9:41 a.m. | Last Modified: 8 Aug 2026, 9:41 a.m.

Panel Version: 9.87

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Phenotypes
inflammatory bowel disease, MONDO:0005265

Publications

• 42259915

Red List (low evidence)

Cui et al. described multiple patients from multiple kindreds, harboring homozygous or compound heterozygous mutations in the GPR15 gene. They presented with severe early-onset inflammatory bowel disease. The underlying mechanism and phenotype were validated in vivo using complete Gpr15 knockout (KO) mouse models, demonstrating impaired colonic homing of regulatory CD8+ TIGR cells, an accumulation of inflammatory macrophages, and increased susceptibility to colitis.
Sources: Literature

Created: 9 Jul 2026, 7:05 p.m.

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Phenotypes
Inflammatory bowel disease; IBD; VEOIBD

Publications

• 42259915