Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: PAX5

I don't know

Comment on list classification: There is only patient and functional evidence available in support of the disease association. Hence, this gene is rated amber on this panel with the current evidence.

Created: 6 Aug 2026, 2:56 p.m. | Last Modified: 6 Aug 2026, 2:56 p.m.

Panel Version: 9.73

PMID:35947077 (2022) reported a male patient with recurrent infections at the age of 2.5 years and was diagnosed initially with hypogammaglobulinemia and later also with autism spectrum disorder, combined with sensorimotor and cognitive deficits. Whole-exome sequencing identified two variants in the PAX5 gene - missense variant c.92G>A (p.Arg31Gln) in the N-terminal part of the DNA-binding paired domain and the nonsense variant c.724G>T (p.Glu242Ter) in the partial homeodomain of PAX5. The asymptomatic mother of the patient carried the Arg31Gln variant, while the de novo variant p.Glu242Ter was also detected in epithelial cells of the patient, suggestive of its sporadic generation in the paternal germline.

The study also showed that the p.Glu242Ter variant is a functional null, while p.Arg31Gln is a hypomorphic allele with reduced DNA binding and transactivation activity, and CRISPR knock-in mouse models (Pax5^R31Q/E242* and Pax5^R31Q/-) recapitulated the patient's B-cell developmental arrest, hypogammaglobulinemia, and cerebellar/midbrain GABAergic neuron loss with ASD-like behaviour.

This gene has not yet been associated with the relevant immunodeficiency phenotype in OMIM (last accessed 06 August 2026). But, it has been associated with PAX5-related B lymphopenia and autism spectrum disorder (MONDO:0100299) by Antibody Deficiencies GCEP in ClinGen with 'moderate' rating (https://search.clinicalgenome.org/CCID:005734)

Created: 6 Aug 2026, 2:54 p.m. | Last Modified: 6 Aug 2026, 2:54 p.m.

Panel Version: 9.71

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
PAX5-related B lymphopenia and autism spectrum disorder, MONDO:0100299; Hypogammaglobulinaemia

Publications

• 35947077

Red List (low evidence)

Kaiser et al. described 1 patient from 1 kindred, harboring compound heterozygous mutations in the PAX5 gene (p.R31Q / p.E242*). They presented with early-onset recurrent infections, severe hypogammaglobulinemia, a profound reduction of peripheral B cells, severely impaired sensorimotor learning, and autism spectrum disorder (ASD).
The underlying mechanism and phenotype were extensively validated using a patient-specific in vivo mutant mouse model (Pax5R31Q/E242* and Pax5R31Q/- mice). These animal models successfully recreated both the immunological and neurological phenotypes, demonstrating an early B-cell developmental block (arrest at the pro-B to pre-B transition), reduced B cell counts in the bone marrow, aberrant cerebellar foliation, and behavioral deficits across ASD domains. Flow cytometry analysis of both the patient's peripheral blood and the murine models confirmed the severe reduction in total B cell numbers and immune arrest. Complete knockout models (Pax5E242*/E242*) demonstrated an absolute failure to generate bone marrow B cells.
Sources: Literature

Created: 17 Jun 2026, 4:13 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
hypogammaglobulinemia; reduced B cells; sensorimotor deficits; autism spectrum disorder

Publications

• 35947077