Clinical significance of genetic mutations in adult patients with focal segmental glomerulosclerosis

Background: Steroid resistance (SR) and a family history of kidney disease (FH) are key clinical indicators of genetic focal segmental glomerulosclerosis (FSGS) in adults.However, the diagnostic yield and prognostic implications of genetic testing in this population remain unclear.Methods: This study was conducted in two parts.Part 1 explored the diagnostic yield of next-generation sequencing (NGS) in adult FSGS patients with SR and/or FH (n=32), who were classified into mutation (n=18) and non-mutation (n=14) groups.Part 2 investigated the clinical significance of different gene mutation types in patients with genetic FSGS (n=19), divided into podocyte-related (PO) and type IV collagen-related (IV-col) gene mutation groups.Clinical, pathological, and prognostic characteristics were compared between groups.Results: In part 1, mutation carriers showed higher FH prevalence (p = 0.03), less acute kidney injury (p = 0.01), milder tubulointerstitial lesions (p = 0.03), and more interstitial foam cell infiltration (p = 0.01).Foam cells strongly predicted genetic FSGS.The mutation group demonstrated superior 2-year kidney survival (p = 0.03), though no long-term advantage.In part 2, IV-col mutations were associated with later onset (p = 0.03), higher serum creatinine (p = 0.01), milder proteinuria (p = 0.02), and heavier hematuria (p = 0.04), with a similar prognosis to the PO group.Conclusion: Genetic testing yields 56.3% in adult FSGS with SR and/or FH.Foam cell infiltration is a strong predictor of genetic etiology.Gene mutations indicate better short-term but not long-term kidney outcomes, and different mutation types show no significant prognostic differences.