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). 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).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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