Clinical and genetic variability of PAX2-related disorder in the Japanese population

J Hum Genet. 2020 Jun;65(6):541-549. doi: 10.1038/s10038-020-0741-y. Epub 2020 Mar 16.

Abstract

Pathogenic variants of paired box gene 2 (PAX2) cause autosomal-dominant PAX2-related disorder, which includes renal coloboma syndrome (RCS). Patients with PAX2-related disorder present with renal and ophthalmological pathologies, as well as with other abnormalities, including developmental problems and hearing loss. We sequenced PAX2 in 457 patients with congenital anomalies of the kidney and urinary tract or with renal dysfunction of unknown cause and identified 19 different pathogenic variants in 38 patients from 30 families (6.5%). Thirty-four patients had renal hypodysplasia or chronic kidney disease of unknown cause, and three had focal segmental glomerulosclerosis. Although no obvious genotype-phenotype correlation was observed, six of the seven patients who developed end-stage renal disease in childhood had truncating variants. Twenty-three patients had ocular disabilities, mostly optic disc coloboma. Non-renal and non-ophthalmological manifestations included developmental disorder, electrolyte abnormality, and gonadal abnormalities. Two unrelated patients had congenital cystic adenomatoid malformations in their lungs. Six of ten probands with PAX2 mutation identified by next-generation sequencing did not show typical RCS manifestations. We conclude that PAX2-related disorder has a variable clinical presentation and can be diagnosed by next-generation sequencing even in the absence of typical RCS manifestations.

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Child, Preschool
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease*
  • Glomerulosclerosis, Focal Segmental / epidemiology
  • Glomerulosclerosis, Focal Segmental / genetics
  • Glomerulosclerosis, Focal Segmental / pathology
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Infant
  • Kidney / metabolism
  • Kidney / pathology*
  • Male
  • Middle Aged
  • Mutation / genetics
  • PAX2 Transcription Factor / genetics*
  • Pedigree
  • Renal Insufficiency, Chronic / epidemiology
  • Renal Insufficiency, Chronic / genetics*
  • Renal Insufficiency, Chronic / pathology
  • Urinary Tract / pathology
  • Young Adult

Substances

  • PAX2 Transcription Factor
  • PAX2 protein, human