Submission Details

Autosomal dominant

03/07/2019

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.

28566479 29036646 29226118 18723445 18849531 11566859