Submission Details

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).