Submission Details

The PAX2 gene is located on chromosome 10 at 10q24.31 and encodes the protein paired box gene 2, which is a transcription factor involved in the development of the urogenital tract, eyes, and central nervous system (CNS). PAX2 mutation was first reported in relation to autosomal dominant papillorenal syndrome in 1995 (Sanyanusin et al., PMID: 7795640). Papillorenal syndrome is characterized by congenital anomalies of kidney and urinary tract (CAKUT), ocular anomalies and high frequency hearing loss. PAX2 mutation has also been reported in association with Focal segmental glomerulosclerosis 7 (first report: Barua et al., PMID: 24676634), characterized by significant protein loss in the urine causing generalized edema. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism and inheritance pattern, and both disease entities have significant phenotypic variability. Therefore, the following disease entities have been lumped into one disease entity, papillorenal syndrome (OMIM:120330) and focal segmental glomerulosclerosis 7 (OMIM:616002). The preferred disease name suggested for this grouping of disorders is ‘Nephropathy, with or without extra-renal features - PAX2’. Sixteen variants (frameshift, nonsense, in-frame insertion, missense, and splice) that have been reported in 18 probands in four publications (PMIDs: 7795640, 9106533, 24676634, 22213154) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is proposed to be loss of function in DNA binding domains of PAX2. This gene-disease association is also supported by animal models, expression studies, in vitro functional assays, and rescue from cell culture models. (PMIDs: 8943028, 17881463, 20221250, 1378753, 1977575, 16368682, 14603255, 30998089). In particular, PAX2 knockout mice caused papillorenal syndrome (PMIDs: 8943028, 17881463, 20221250) and PAX2 expression was demonstrated in normal human kidney and mouse CNS during nephrogenesis and neurogenesis respectively (PMIDs: 1378753, 1977575). Furthermore, in-vitro functional assays demonstrated PAX2 interaction with WNT4 (PMID: 16368682), which is critical for nephrogenesis, and WT1 (PMID: 14603255), which activates podocyte proteins nephrin and podocalyxin. Lastly, PAX2 missense mutation corrected by CRISPR-Cas9 rescued podocyte mobility in a cell culture model (PMID: 30998089). In summary, PAX2 is definitively associated with autosomal dominant nephropathy, with or without extra-renal features - PAX2. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.