Kareshma Asharam 1 , Rajendra Bhimma 1 , Victor A. David 2 , Hoosen M. Coovadia 1 , 3 , Wenkosi P. Qulu 1 , Thajasvarie Naicker 1 , Christopher E. Gillies 4 , Virginia Vega-Warner 4 , Randall C. Johnson 5 , Sophie Limou 6 , Jeffrey B. Kopp 7 , Mathew Sampson 4 , George W. Nelson 5 , Cheryl A. Winkler 6 , ∗
29 July 2018
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 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.
Homozygosity 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.
NPHS2 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.