PAX5

Inheritance Pattern: AR

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0014241

Submitter: ClinGen

PAX5 was first reported in relation to autosomal dominant PAX5-related leukemia predisposition in 2013 (Shah et al., PMID: 24013638). Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found differences in inheritance pattern and phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities, PAX5-related B lymphopenia and autism spectrum disorder, neurodevelopmental disorders/autism spectrum disorder and PAX5-related B-cell acute lymphoblastic leukemia predisposition. The split curation for autosomal recessive PAX5-related B lymphopenia and autism spectrum disorder has been curated separately by the antibody Deficiencies GCEP. The neurodevelopmental disorders/autism spectrum disorder assertion might be curated separately by another ClinGen GCEP. The mechanism of pathogenicity is reported to be loss of function. Nine variants (missense, frameshift, large deletion, splice variant) that have been reported in 30 probands in 10 publications (PMIDs: 24013638, 24287434, 35902733, 33036026, 26782422, 38571503, 37543654, 26115422, 39256601) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached (PMID: 29847298). This gene-disease relationship is also supported by experimental evidence including animal models, expression studies and biochemical evidence studies (PMIDs: 30643249, 17851532, 17600970, 17658281). In summary, there is definitive evidence supporting the relationship between PAX5 and B-cell acute lymphoblastic leukemia predisposition. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Childhood, Adolescent, and Young Adult Cancer Predisposition GCEP on the meeting date May 13, 2025 (SOP Version 11).

Inheritance Pattern: AD

Disease ID:MONDO:0014241

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0014241

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: Broad Center for Mendelian Genomics

Inheritance Pattern: AR

Disease ID:MONDO:0100299

Submitter: ClinGen

*PAX5* was first reported in relation to B lymphopenia and autism spectrum disorder (ASD) in 2022 (Kaiser FMP, et al., 2022, PMID: 35947077). This is the only patient reported to date; two variants (one hypomorphic missense variant and one null nonsense variant) were reported in this proband (PMID: 35947077). Experimentally, this gene-disease relationship is supported by its expression pattern and biochemical function. During embryogenesis, the transcription factor Pax5 is expressed, together with the related Pax2 protein, in the isthmic organizer at the midbrain–hindbrain boundary, from which the cerebellum, and within the hematopoietic system, Pax5 is exclusively expressed in the B lymphoid lineage (PMID: 17600970). At the molecular level, Pax5 performs a dual role in B lymphopoiesis by acting as a transcriptional repressor to suppress B lineage–inappropriate genes and as an activator to induce gene expression required for B cell development and function (PMID: 17658281). In patient cells the residual mature B cells of the patient were impaired in their function due to the observed PI3K signaling defect (PMID: 35947077). Furthermore, in mouse models both Pax5R31Q/E242* and Pax5R31Q/− mutant mice, with patient derived mutations, revealed an early B cell developmental block and impaired immune responses as the cause of hypogammaglobulinemia (PMID: 35947077) and Pax5R31Q/− mutant mice exhibited aberrant social and stereotypical behavior and cognitive deficits. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. Of note, *PAX5* has also been identified as a candidate ASD risk gene with de novo heterozygous loss of function variants in 8PAX58 identified in large cohorts of individuals with ASD (Gofin et al., 2022; Iossifov et al., 2012; O’Roak et al., 2014; Stessman et al., 2017). This curation only considered *PAX5* variation related to a monogenic form of ASD accompanied by hypogammaglobulinemia. Another important function of Pax5, not considered in this curation, is to suppress B cell tumorigenesis in mice (Cobaleda et al., 2007) and humans (Mullighan et al., 2007), where heterozygous *PAX5* mutations prominently contribute to the development of B cell acute lymphoblastic leukemia (Gu et al., 2019).

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: PanelApp Australia