Effect of combined NPHS2 and ACTN4 variants in the onset and severity of focal segmental glomerulosclerosis

Introduction: Focal segmental glomerulosclerosis (FSGS) can be caused by mutations in the genes NPHS2, ACTN4, TRPC6, and INF2 among others, presenting variable levels of proteinuria, including nephrotic syndrome, that frequently progress to end-stage renal disease (ESRD). The establishment of the genotype-phenotype correlation caused by mutations in genes expressed in the podocyte could contribute to understanding their role in FSGS and to the decision-making in the clinical setting in similar cases. Methods: Genomic DNA was extracted from peripheral blood of the proband, his brother, sister and mother. All the exons of the genes NPHS2, ACTN4, TRPC6, and INF2 were amplified by a polymerase chain reaction, purified, and sequenced by the Sanger method. The presence of variants was evaluated in the proband with FSGS and relatives, reviewed, and annotated using dbSNP and HGMD. Results: In the clinical evaluation, the proband and his brother presented childhood-onset nephrotic syndrome, added with renal biopsies confirming FSGS, which was resistant to steroid and other immunosuppressive drugs, and progressed to ESRD. Both patients showed the variants p.P316S in NPHS2 and p.G894S in ACTN4, as well as the polymorphism p.R229Q in NPHS2, all variants in heterozygosis. Their parents were healthy, and the mother presented only the variant p.P316S in NPHS2 in heterozygosis. Conclusions: The family members with FSGS had a combination of the variants p.P316S and p.R229Q in NPHS2, and p.G894S in ACTN4, shared similar clinical presentation, nephrotic syndrome with onset in late childhood that rapidly progressed to ESRD.