Interpretative Challenges of Variants of Uncertain Significance in Severe Treatment-Refractory Focal Segmental...

Steroid-resistant nephrotic syndrome (SRNS) frequently reflects an underlying monogenic podocytopathy; however, the increasing use of genomic testing has also led to frequent identification of variants of uncertain significance (VUS), complicating clinical interpretation and creating a risk of overattribution of causality.

We report a 22-year-old woman with childhood-onset nephrotic syndrome evolving along the focal segmental glomerulosclerosis spectrum and refractory to multiple immunosuppressive agents, including corticosteroids, calcineurin inhibitors, mycophenolate mofetil, and rituximab. Despite prolonged therapy, she had persistent nephrotic-range proteinuria and severe hypoalbuminemia. Her clinical course was complicated by recurrent infections, necrotizing pancreatitis attributed to calcineurin inhibitor exposure, and thromboembolic events - including deep vein thrombosis and ischemic stroke - in the setting of nephrotic hypercoagulability. She subsequently developed a spontaneous hydropneumothorax during a period of severe disease activity. Kidney function remained preserved throughout follow-up. Comprehensive genomic testing identified heterozygous VUS in ARHGAP24 and NUP133.

This case illustrates the interpretative challenges posed by VUS in complex glomerular disease and underscores the need for disciplined variant classification, careful gene-disease validation, and rigorous clinical-genetic correlation to avoid misclassification and inappropriate management decisions in SRNS.