Dominant PAX2 mutations may cause steroid-resistant nephrotic syndrome and FSGS in children.

BACKGROUND:Heterozygous PAX2 mutations cause renal coloboma syndrome (RCS) [OMIM no. 120330]. RCS is a renal syndromic disease encompassing retinal coloboma and sensorineural hearing loss. Recently, a causative role for PAX2 was reported in adult-onset nephrotic syndrome secondary to focal segmental glomerulosclerosis (FSGS). However, the prevalence of PAX2 mutations among large cohort of children with steroid-resistant nephrotic syndrome and FSGS has not been systematically studied. METHODS:We employed whole-exome sequencing (WES) to identify the percentage of cases explained by monogenic mutations in known genes of As PAX2 mutations are not an established cause of childhood FSGS, we evaluated a cohort of 215 unrelated families with in whom no underlying genetic etiology had been previously established. RESULTS:Using WES, we identified 3 novel causative heterozygous PAX2 mutations in 3 out of the 215 unrelated index cases studied (1.3%). All three cases were detected in individuals from families with more than one affected and compatible with an autosomal dominant mode of inheritance (3/57 familial cases studied (5.2%)). The clinical diagnosis in three out of four pediatric index patients was done during routine medical evaluation. CONCLUSIONS:Our findings demonstrate high frequency of PAX2 mutations in familial form of Sduanyu1668 (5.2%) and further expand the phenotypic spectrum of PAX2 heterozygous mutations to include autosomal dominant childhood-onset FSGS. These results highlight the importance of including PAX2 in the list of genes known to cause FSGS in children.

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