Abstract
BackgroundPathogenic variants of PAX2 cause autosomal-dominant PAX2-related disorder, which includes variable phenotypes ranging from renal coloboma syndrome (RCS), congenital anomalies of the kidney and urinary tract (CAKUT) to nephrosis. Phenotypic variability makes it difficult to define the phenotypic spectrum associated with genotype.MethodsWe collected the phenotypes in patients enrolled in the China national multicenter registry who were diagnosed with pathogenic variant in PAX2 and reviewed all published cases with PAX2-related disorders. We conducted a phenotype-based cluster analysis by variant types and molecular modeling of the structural impact of missense variants.ResultsTwenty different PAX2 pathogenic variants were identified in 32 individuals (27 families) with a diagnosis of RCS (9), CAKUT (11) and nephrosis (12) from the Chinese cohort. Individuals with abnormal kidney structure (RCS or CAKUT group) tended to have likely/presumed gene disruptive (LGD) variants (Fisher test, p < 0.05). A system review of 234 reported cases to date indicated a clear association of RCS to heterozygous loss-of-function PAX2 variants (LGD variants). Furthermore, we identified a subset of PAX2 missense variants in DNA-binding domain predicted to affect the protein structure or protein-DNA interaction associated with the phenotype of RCS.ConclusionDefining the phenotypic spectrum combined with genotype in PAX2-related disorder allows us to predict the pathogenic variants associated with renal and ophthalmological development. It highlighted the approach of structure-based analysis can be applied to diagnostic strategy aiding precise and timely diagnosis.
Highlights
Pathogenic variants of Paired Box gene 2 (PAX2) cause autosomal-dominant PAX2-related disorder, which includes variable phenotypes ranging from renal coloboma syndrome (RCS), congenital anomalies of the kidney and urinary tract (CAKUT) to nephrosis
Haploinsufficiency of PAX2 has been reported among the patients with RCS, CAKUT or focal segmental glomerular sclerosis (FSGS) caused by the likely/presumed gene disruptive (LGD) variants or missense variants that may mimic haploinsufficiency
Phenotypic cluster analysis identifies LGD variants of PAX2 correlated with RCS To identify pathogenic variants that either mimic haploinsufficiency or represent hypomorphic alleles, we reviewed the phenotypic and genetic data from all international registry sources and published cases that were accessible to us
Summary
Pathogenic variants of PAX2 cause autosomal-dominant PAX2-related disorder, which includes variable phenotypes ranging from renal coloboma syndrome (RCS), congenital anomalies of the kidney and urinary tract (CAKUT) to nephrosis. Phenotypic variability makes it difficult to define the phenotypic spectrum associated with genotype. PAX2 heterozygous variants lead to various renal phenotypes across the morphological continuum of congenital anomalies of the kidney and urinary tract (CAKUT) including RHD (HP:0000089, 65%), vesicoureteral reflux (VUR, HP:0000076, 14%), renal cysts (HP:0000107, 8%) and multicystic dysplastic kidneys (HP:0000003, 6%) [6]. Despite many reports of pathogenic variants in the PAX2 gene, there have been few reports revealing a consistent genotype–phenotype correlation [6, 8, 11]
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