Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: ITPR3

Green List (high evidence)

The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.

Created: 24 Feb 2025, 12:01 p.m. | Last Modified: 24 Feb 2025, 12:01 p.m.

Panel Version: 7.26

Comment on list classification: The availability of four unrelated cases reported with the same de novo dominant-negative variant and supporting functional studies for this variant provides sufficient evidence for monoallelic MOI.

The presence of two unrelated cases reported with compound heterozygous variants and supporting functional work provides sufficient evidence for biallelic MOI.

Hence, the MOI was set to "BOTH monoallelic and biallelic, autosomal or pseudoautosomal" and the gene has been recommended for promotion to green rating in the next GMS update.

Created: 9 Oct 2024, 5:46 p.m. | Last Modified: 9 Oct 2024, 5:46 p.m.

Panel Version: 6.16

PMID:36302985 reported the identification of three different ITPR3 variants in two unrelated male patients at compound heterozygous state. The 12-year-old patient presented with combined immunodeficiency with profoundly low numbers of B and T cells and required hematopoietic stem cell transplantation (HSCT) at the age of 6 years. The 36-year-old patient resented with recurring immune thrombocytopenia (ITP), requiring splenectomy at the age of 19 years. He subsequently suffered from autoimmune hemolytic anemia, susceptibility to infections, and enteropathy. Hypogammaglobulinemia and low numbers of switched memory B cells led to a diagnosis of CVID and monthly treatment with intravenous immunoglobulin. The patient did not show signs of neuromuscular disorder. Functional work demonstrated that these variants impaired IP3-mediated Ca2+ responses in vitro, translating into deficient T-cell activation and proliferation.

PMID:39270020 reported the identification of the same ITPR3 de novo variant (p.Arg2524Cys) in four unrelated patients and they presented with a complex syndromic immunodeficiency with variable multisystemic manifestations including ectodermal dysplasia, Charcot-Marie-Tooth disease, short stature, and bone marrow failure. Functional studies in patient-derived cells and gene-edited Jurkat cell lines confirmed that this variant alone is responsible for and capable of disturbing intracellular calcium homeostasis and hence ultimately the clinical phenotype. In addition, functional work also showed that this variant exhibits a dominant-negative effect.

Neither monoallelic nor biallelic variants in this gene has been associated with immunodeficiency phenotypes either in OMIM or in Gene2Phenotype.

Created: 9 Oct 2024, 10 a.m. | Last Modified: 9 Oct 2024, 5:34 p.m.

Panel Version: 6.12

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
combined immunodeficiency, MONDO:0015131

Publications

• 36302985
• 39270020

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

Green List (high evidence)

PMID: 39270020 Described 4 cases with the dame de novo variant and a complex phenotype including immunodeficiency + functional work. Enought for green rating
Sources: Literature

Created: 16 Sep 2024, 3:38 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Multisystemic

Publications

• PMID: 39270020

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments