Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: SIT1

I don't know

Comment on list classification: There is only one case and functional evidence reported in support of the association of SIT1 gene with combined immunodeficiency. Hence, this gene should be rated amber with the current evidence.

Created: 7 Aug 2026, 2:53 p.m. | Last Modified: 7 Aug 2026, 2:53 p.m.

Panel Version: 9.83

PMID:42128181 (2026) reported a male patient of Finnish descent presenting with recurrent Hodgkin lymphoma, predisposition to human papillomavirus (HPV) infection and combined immunodeficiency and identified with a homozygous splice-donor variant in SIT1 gene (c.236+2T>G). Targeted capillary sequencing confirmed inheritance from heterozygous, unaffected parents and identified the brother as a variant carrier. This variant is enriched in the Finnish population (0.35% vs 0.014% globally), with 230 heterozygotes and no homozygotes in gnomAD v4.1.0.

Functional studies showed exon 2 skipping, loss of SIT1 protein, hyperactive T-cell responses, and recapitulation of the phenotype in CRISPR-Cas9 SIT1-knockout donor T-cells, with partial rescue by SIT1 mRNA.

This gene has not been associated with relevant phenotypes either in OMIM or in ClinGen (last accessed 07 August 2026).

Created: 7 Aug 2026, 2:51 p.m. | Last Modified: 7 Aug 2026, 2:51 p.m.

Panel Version: 9.81

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
combined immunodeficiency, MONDO:0015131

Publications

• 42128181

Red List (low evidence)

Pu Chen et al. described 1 patient from 1 kindred, harboring homozygous mutations in the SIT1 gene. They presented with combined immune deficiency and recurrent Hodgkin lymphoma. The underlying mechanism and phenotype were validated ex vivo using patient-derived lymphocytes and in vitro using CRISPR-Cas9-mediated SIT1 knockout T cells from healthy donors, demonstrating skewed T cell subsets, increased activation and proliferation, impaired CD8+ cytotoxicity, and defective immune synapse maturation with vesicle accumulation upon T cell receptor stimulation. The phenotype was successfully recreated with complete knockout models.
Sources: Literature

Created: 23 Jun 2026, 9:25 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Combined immunodeficiency; Hodgkin lymphoma; Abnormal T cell physiology; Impaired CD8+ T cell cytotoxicity

Publications

• 42128181