Causal and putative pathogenic mutations identified in 39% of children with primary steroid-resistant nephrotic syndrome in South Africa

There is a paucity of data identifying genetic mutations that account for the high rate of steroid-resistant nephrotic syndrome (SRNS) in a South African paediatric population. The aim was to identify causal mutations in genes implicated in SRNS within a South African paediatric population. We enrolled 118 children with primary nephrotic syndrome (NS), 70 SRNS and 48 steroid-sensitive NS. All children with SRNS underwent kidney biopsy. We first genotyped the NPHS2 gene for the p.V260E variant in all NS cases (n = 118) and controls (n = 219). To further identify additional variants, we performed whole-exome sequencing and interrogated ten genes (NPHS1, NPHS2, WT1, LAMB2, ACTN4, TRPC6, INF2, CD2AP, PLCE1, MYO1E) implicated in SRNS with histopathological features of focal segmental glomerulosclerosis (FSGS) in 56 SRNS cases and 29 controls; we also performed exome sequencing on two patients carrying the NPHS2 p.V260E mutation as positive controls. The overall detection rate of causal and putative pathogenic mutations in children with SRNS was 27/70 (39%): 15 (21%) carried the NPHS2 p.V260E causal mutation in the homozygous state, and 12 (17%) SRNS cases carried a putative pathogenic mutation in the heterozygous state in genes (INF2 (n = 8), CD2AP (n = 3) and TRPC6 (n = 1)) known to have autosomal dominant inheritance mode. NPHS2 p.V260E homozygosity was specifically associated with biopsy-proven FSGS, accounting for 24% of children of Black ethnicity (15 of 63) with steroid-resistant FSGS. No causal or putative pathogenic mutations were identified in NPHS1, WT1, LAMB2, PLCE1, MYO1E and ACTN4. We report four novel variants in INF2, PLCE1, ACTN4 and TRPC6. Conclusion: We report putative missense variants predicted to be pathogenic in INF2, CD2AP and TRPC6 among steroid-resistant-FSGS children. However, the NPHS2 p.V260E mutation is a prevalent cause of steroid-resistant FSGS among Black South African children occurring in 24% of children with SRNS. Screening all Black African children presenting with NS for NPHS2 p.V260E will provide a precision diagnosis of steroid-resistant FSGS and inform clinical management. What is Known: • Limited data is available on the genetic disparity of SNRS in a South African paediatric setting. • The high rate of steroid resistance in Black South African children with FSGS compared to other racial groups is partially explained by the founder variant NPHS2 p.V260E. What is New: • We report putative missense variants predicted to be pathogenic in INF2, CD2AP and TRPC6 among steroid-resistant FSGS children. • NPHS2 p.V260E mutation remains a prevalent cause of steroid-resistant FSGS among Black South African children, demonstrating precision diagnostic utility.