Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: ZBTB7B

I don't know

Comment on list classification: A single patient case and functional evidence available in support of the association of ZBTB7B gene with inborn error of immunity. Hence, this gene should be rated amber with the current evidence on this panel.

Created: 7 Aug 2026, 3:27 p.m. | Last Modified: 7 Aug 2026, 3:27 p.m.

Panel Version: 9.86

PMID:40392549 (2025) reported a 5-year-old male patient with a novel combined immunodeficiency/ allergic/ fibrotic syndrome, and identified with a de novo heterozygous missense variant (c.1080A>C/ p.Lys360Asn) by trio whole-genome sequencing. The patient presented with CD4+ T-cell lymphopenia, CD8+ lymphocytosis, severe early-onset allergic disease, fibroinflammatory interstitial lung disease, corneal defects, sensorineural hearing loss, and global developmental delay.

Extensive functional studies supported a multimorphic mechanism combining dominant-negative, loss-of-function, and neomorphic gain-of-function effects on DNA binding and downstream gene targets. The causal link between K360N and the clinical phenotype was supported by lentiviral gene-transfer experiments in both healthy-donor T cells and pulmonary fibroblasts, which reproduced disease-relevant molecular defects (abnormal TCR-activation transcriptomics and a profibrotic gene signature, respectively).

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

Created: 7 Aug 2026, 3:15 p.m. | Last Modified: 7 Aug 2026, 3:15 p.m.

Panel Version: 9.83

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
inborn error of immunity, MONDO:0003778; interstitial lung disease, MONDO:0015925; Global developmental delay, HP:0001263

Publications

• 40392549

Red List (low evidence)

Vaseghi-Shanjani et al. described 1 patient from 1 kindred, harboring a de novo heterozygous mutation in the ZBTB7B gene encoding ThPOK. They presented with persistent CD4+ T cell deficiency, allergy, interstitial lung disease, corneal vascularization and scarring, developmental delay, and growth failure. The underlying mechanism and phenotype were validated in vitro using lentivirally transduced healthy control T cells and fibroblasts, demonstrating impaired T cell receptor activation and increased profibrotic gene expression. The study did not specify whether the phenotype was successfully recreated with complete knockout (KO) models or if the defect was corrected via rescue experiments.
Sources: Literature

Created: 1 Jul 2026, 5:02 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
CD4+ T-cell deficiency; Allergic disease; Interstitial lung disease; Corneal neovascularization; Corneal scarring; Global developmental delay; Growth failure

Publications

• 40392549