PBX1

Inheritance Pattern: AD

Disease ID:MONDO:0060549

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0060549

Submitter: ClinGen

The *PBX1* gene is located on chromosome 1 at 1q23.3 and encodes the PBX homeobox 1 protein, a homeodomain transcription factor that forms multimeric complexes with TALE and HOX proteins to regulate gene transcription during development. *PBX1* is specifically involved in body axes patterning and organogenesis (Stankunas et al., 2008, PMID: 18723445; Schnabel et al., 2003, PMID: 12591246; Capellini et al., 2008, PMID: 18691704). *PBX1* was first reported in relation to autosomal dominant *PBX1*-related intellectual disability and pleiotropic developmental defects disorder in 2017 (Heidet et al., 2017, PMID:28566479). Congenital heart disease is also observed in patients, including atrial septal defect, ventricular septal defect, coarctation of aorta, overriding aorta, tetralogy of Fallot, Ebstein anomaly, absent pulmonary valve, and, only in combination with other cardiac features, patent ductus arteriosus (PMIDs: 29036646, 32141698, 34797033; DOI: 10.1016/j.gimo.2024.101705). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Seven variants including 2 frameshift, 2 nonsense, 1 essential splice site, and 2 missense have been reported in 8 probands with a spectrum of intellectual disability and pleiotropic developmental defects in 3 publications (PMID: 28566479; Slavotinek et al., 2017, PMID: 29036646; Safgren et al., 2022, PMID: 34797033) are included in this curation. More genetic evidence has been reported in the literature, but the maximum score for this category has been reached (12 pts). Experimental evidence includes protein interaction, biochemical function and a mouse model. There is extensive protein interaction with over 90 cofactors or target proteins, which includes Hox proteins, FLNA and CREB-binding proteins (Mary et al., 2022, PMID: 35451537). A homozygous knock-in mouse model expressing a variant found in an affected individual phenocopies multiple congenital and developmental anomalies, consistent with the clinical spectrum of disease (Chang et al., 2008, PMID: 18849531). In summary, *PBX1* is definitively associated with autosomal dominant congenital anomalies of kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay (CAKUT). This relationship 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 Syndromic Disorders Gene Curation Expert Panel on the meeting date 11.18.2022 (SOP Version 9.0). This curation was re-evaluated by the ClinGen Congenital Heart Disease GCEP on 7/14/2025 (SOP Version 11).

Inheritance Pattern: AD

Disease ID:MONDO:0060549

Submitter: Illumina

The PBX1 gene is located on chromosome 1 at 1q23.3 and encodes the PBX homeobox 1 protein, a homeodomain transcription factor that forms multimeric complexes with TALE and HOX proteins to regulate gene transcription during development. PBX1 is specifically involved in body axes patterning and organogenesis (12591246: Schnabel 2003; 18723445: Stankunas et al. 2008). PBX1 was first reported in relation to autosomal dominant PBX1-related congenital anomalies of kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay in 2017 (28566479: Heidet et al. 2017). Evidence supporting this gene-disease relationship includes case-level data and experimental data. At least seven de novo variants, in a heterozygous state, have been found in seven cases with a spectrum of intellectual disability and pleiotropic developmental defects, from three reports in the literature (28566479: Heidet et al. 2017; 29036646: Slavotinek et al. 2017; 29226118: Riedhammer et al. 2017). These included three missense variants, a nonsense variant, two small deletions leading to a frameshift, and a splicing variant. More genetic evidence has been reported in the literature, but the maximum score for this category has been reached (12 pts). Expression data in the mouse and phenotype data from the homozygous null mouse model demonstrated that the Pbx1 protein is expressed in multiple tissues during embryogenesis and is required for the correct patterning and development of multiple organs as well as skeletal development, which is consistent with the clinical spectrum of disease (11566859: Selleri et al. 2001; 18723445: Stankunas et al. 2008; 18849531: Chang et al. 2008). In summary, there is strong evidence to support the relationship between PBX1 and autosomal dominant PBX1-related congenital anomalies of kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay. Three years must elapse from the first proposal of the association to reach a definitive classification.

Inheritance Pattern: AD

Disease ID:MONDO:0060549

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0060549

Submitter: PanelApp Australia