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

• Published in: Kidney international reports Vol. 3; no. 6; pp. 1354 - 1362
• Main Authors: Asharam, Kareshma, Bhimma, Rajendra, David, Victor A., Coovadia, Hoosen M., Qulu, Wenkosi P., Naicker, Thajasvarie, Gillies, Christopher E., Vega-Warner, Virginia, Johnson, Randall C., Limou, Sophie, Kopp, Jeffrey B., Sampson, Mathew, Nelson, George W., Winkler, Cheryl A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier 01.11.2018
• Subjects: Clinical Research; steroid resistance; FSGS; APOL1; NPHS2; nephrotic syndrome; CD2AP
• ISSN: 2468-0249; 2468-0249
• DOI: 10.1016/j.ekir.2018.07.017

In South Africa (SA), steroid-resistant nephrotic syndrome (SRNS) is more frequent in black than in Indian children. Seeking 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 and genotyped 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. Homozygosity for 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 260E/E developed SRNS at earlier age than noncarriers (34 vs. 78 months,  = 0.01), and none achieved partial or complete remission (0% vs. 47%,  = 0.002). variants did not associate with NS. Sequencing FSGS genes identified a predicted pathogenic variant in the heterozygous state in 1 Indian case with SR-FSGS. 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.