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

Area of Science:

• Genetics
• Pediatric Nephrology
• Molecular Biology

Background:

• Heterozygous PAX2 mutations are linked to renal coloboma syndrome (RCS), characterized by eye and kidney abnormalities.
• PAX2 mutations have been recently associated with adult-onset nephrotic syndrome due to focal segmental glomerulosclerosis (FSGS).
• The prevalence of PAX2 mutations in pediatric steroid-resistant nephrotic syndrome (SRNS) and FSGS remains understudied.

Purpose of the Study:

• To determine the frequency of monogenic mutations in known SRNS/FSGS genes using whole-exome sequencing (WES).
• To investigate the role of PAX2 mutations in a cohort of 215 unrelated families with SRNS, where the genetic cause was previously unknown.

Main Methods:

• Whole-exome sequencing (WES) was performed on 215 unrelated families with SRNS.
• The cohort included families with no previously established genetic etiology for their condition.

Main Results:

• Three novel heterozygous PAX2 mutations were identified in 3 out of 215 index cases (1.3%).
• All identified cases involved familial forms with an autosomal dominant inheritance pattern (5.2% of familial cases).
• Clinical diagnoses in pediatric patients were often made during routine medical evaluations.

Conclusions:

• PAX2 mutations are frequently found in the familial form of SRNS (5.2%).
• These findings expand the phenotypic spectrum of PAX2 mutations to include autosomal dominant childhood-onset FSGS.
• PAX2 should be considered in the genetic evaluation of children diagnosed with FSGS.