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

Pediatr Nephrol. 2019 Sep;34(9):1607-1613. doi: 10.1007/s00467-019-04256-0. Epub 2019 Apr 17.

Abstract

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 (SRNS) and FSGS has not been systematically studied.

Methods: We employed whole-exome sequencing (WES) to identify the percentage of SRNS cases explained by monogenic mutations in known genes of SRNS/FSGS. As PAX2 mutations are not an established cause of childhood FSGS, we evaluated a cohort of 215 unrelated families with SRNS, 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 SRNS (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.

Keywords: Congenital anomalies of the kidneys and urinary tract (CAKUT); FSGS; SRNS and PAX2.

Publication types

  • Observational Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Age of Onset
  • Child
  • Child, Preschool
  • Cohort Studies
  • DNA Mutational Analysis
  • Drug Resistance / genetics
  • Female
  • Genetic Predisposition to Disease*
  • Genetic Testing
  • Glomerulosclerosis, Focal Segmental / genetics*
  • Glucocorticoids / pharmacology*
  • Glucocorticoids / therapeutic use
  • Heterozygote
  • Humans
  • Infant
  • Male
  • Mutation
  • Nephrotic Syndrome / drug therapy
  • Nephrotic Syndrome / genetics*
  • PAX2 Transcription Factor / genetics*
  • Pedigree
  • Whole Exome Sequencing
  • Young Adult

Substances

  • Glucocorticoids
  • PAX2 Transcription Factor
  • PAX2 protein, human