NPHS2 V260E Is a Frequent Cause of Steroid-Resistant Nephrotic Syndrome in Black South African Children

Abstract

IntroductionIn South Africa (SA), steroid-resistant nephrotic syndrome (SRNS) is more frequent in black than in Indian children.MethodsSeeking a genetic basis for this disparity, we enrolled 33 Indian and 31 black children with steroid-sensitive nephrotic syndrome (SSNS) and SRNS from KwaZulu-Natal, SA; SRNS children underwent kidney biopsy. We sequenced NPHS2 and genotyped APOL1 in 15 SSNS and 64 SRNS unrelated patients and 104 controls and replicated results in 18 black patients with steroid-resistant focal segmental glomerulosclerosis (SR-FSGS). Known FSGS genes (n = 21) were sequenced in a subset of patients.ResultsHomozygosity for NPHS2 V260E was found in 8 of 30 black children with SRNS (27%); all 260E/E carriers had SR-FSGS. Combining SR-FSGS patients from the 2 groups, 14 of 42 (33%) were homozygous for V260E. One black control was heterozygous for V260E; no Indian patients or controls were carriers. Haplotype analysis indicated that homozygosity for V260E was not explained by cryptic consanguinity. Children with NPHS2 260E/E developed SRNS at earlier age than noncarriers (34 vs. 78 months, P = 0.01), and none achieved partial or complete remission (0% vs. 47%, P = 0.002). APOL1 variants did not associate with NS. Sequencing FSGS genes identified a CD2AP predicted pathogenic variant in the heterozygous state in 1 Indian case with SR-FSGS.ConclusionNPHS2 260E/E was present in one-third of black FSGS patients, was absent in black controls and Indian patients, and affected patients were unresponsive to therapy. Genotyping V260E in black children from South Africa with NS will identify a substantial group with SR-FSGS, potentially sparing these children biopsy and ineffective steroid treatment.

Nephrotic syndrome‐associated hypercoagulopathy is alleviated by both pioglitazone and glucocorticoid which target two different nuclear receptors

“…As expected (Eddy & Symons, 2003), the children with SRNS were significantly older at presentation, otherwise the groups were demographically similar. Genetics are known to play a role in steroid-responsiveness (Adeyemo et al, 2018;Asharam et al, 2018;Govender et al, 2019;Gribouval et al, 2018Gribouval et al, , 2019. However, while genetic and other mechanisms underlying steroid-responsiveness in this small cohort were not evaluated in the present study, they have been the subject of previously reported biomarker studies (Agrawal et al, 2020;Gooding et al, 2020).…”

Nephrotic Syndrome in South African Children: Changing Perspectives in the New Millennium

“…All those with NPHS2 260E/E mutation were unresponsive to therapy. The authors concluded that genotyping V260E in Black children from South Africa with NS would identify a sizable proportion of Black children with steroid-resistant FSGS, potentially sparing these children the use of steroids and other immunosuppressive agents as well as the need to undergo kidney biopsy, which is an invasive procedure 54 …”

The podocin V260E mutation predicts steroid resistant nephrotic syndrome in black South African children with focal segmental glomerulosclerosis

“…In South Africa, there are limited genetic studies on kidney disease, including FSGS, among children. Asharam et al (2018) 20 reported on 33 Indian and 31 black children from Kwa-Zulu Natal with SSNS and SRNS. In their study, APOL1 variants were not associated with NS, but the NPHS2 V260E allele was specifically associated with SRNS (with FSGS) in black children; 8 were homozygous for the variant (OR 21; 95% CI, 2.8–960) and no heterozygotes were observed.…”