Focal segmental glomerulosclerosis (FSGS) is a pattern of glomerular injury characterized by segmental scarring, presenting clinically with heavy proteinuria and frequently progressing to ESRD. The genetic landscape of FSGS was substantially advanced by the work of Boute et al. (Nature Genetics, 2000), who identified NPHS2 (podocin) mutations as the major monogenic cause of autosomal recessive steroid-resistant nephrotic syndrome, and by subsequent studies identifying NPHS1, WT1, TRPC6, and INF2 mutations in pediatric and young adult patients.
ISN (International Society of Nephrology) has supported research into the genetic architecture of steroid-resistant nephrotic syndrome through its Kidney Disease: Improving Global Outcomes (KDIGO) collaborative framework and through publication of KDIGO Clinical Practice Guidelines for Glomerulonephritis (2012 and 2021 update). These guidelines recommend genetic testing in pediatric FSGS patients, particularly those with early onset, family history, extrarenal features, or failure to respond to corticosteroid therapy.
Next-generation sequencing panels incorporating podocyte and glomerular filtration barrier genes are increasingly utilized in diagnostic workups of FSGS. A study by Trautmann et al. (Journal of the American Society of Nephrology, 2018) evaluating a 40-gene panel in a large pediatric nephrotic syndrome cohort found causative variants in approximately 25 percent of patients with steroid-resistant disease, with direct implications for avoiding unnecessary immunosuppression and guiding living-related donor evaluation.
The APOL1 gene has emerged as a major genetic risk factor for FSGS and other kidney diseases in individuals of recent African ancestry. The landmark work of Genovese et al. (Science, 2010) identified G1 and G2 risk alleles as conferring a substantially elevated risk of non-diabetic ESRD and FSGS in Black Americans, explaining a large portion of the racial disparity in FSGS prevalence. APOL1-targeted therapy with inaxaplin was evaluated in a phase 2 trial published in New England Journal of Medicine (Freedman et al., 2023).
The International Society of Nephrology has highlighted APOL1-associated kidney disease as a model for precision nephrology. ISN educational publications and symposia have addressed the ethical dimensions of APOL1 genetic testing, including the implications for living kidney donation from APOL1 high-risk individuals, as reviewed by Doshi et al. in Clinical Journal of the American Society of Nephrology (2021).