Variability in phenotype induced by the podocin variant R229Q plus a single pathogenic mutation

Area of Science:

• Genetics
• Pediatric Nephrology
• Molecular Biology

Background:

• Mutations in podocin (NPHS2) are a leading cause of childhood-onset steroid-resistant nephrotic syndrome (SRNS).
• SRNS is marked by early proteinuria, immunosuppression resistance, and rapid progression to end-stage renal disease.
• The R229Q podocin variant, when compound heterozygous with another pathogenic mutation, has been linked to milder phenotypes with adult onset.

Purpose of the Study:

• To investigate the clinical spectrum of NPHS2 mutations, particularly the R229Q variant.
• To identify genetic causes of early-onset SRNS in families.

Main Methods:

• Genetic screening of 19 families with early-onset SRNS for mutations in NPHS2 and WT1.
• Identification of disease-causing mutations through targeted gene analysis prior to whole-exome sequencing.

Main Results:

• Identified three pathogenic NPHS2 mutations (R229Q combined with L327F or A297V) in two families with three children presenting with SRNS.
• One child (A297V plus R229Q) presented at age 4, and two children (L327F plus R229Q) presented at age 13.
• One of the affected children exhibited steadily deteriorating renal function.

Conclusions:

• These findings underscore the significant phenotypic variability associated with compound heterozygous NPHS2 mutations involving R229Q.
• Individuals carrying these mutations can present with early-onset and aggressive forms of nephrotic syndrome.