NPHS2 homozygous p.R229Q variant: potential modifier instead of causal effect in focal segmental glomerulosclerosis

Background The pathogenicity of the NPHS2 homozygous p.R229Q variant in steroid-resistant nephrotic syndrome (SRNS) is doubtful. While it has been reported in unaffected controls, it is enriched in patients with SRNS, suggesting pathogenicity. Case-Diagnosis/Treatment A family with three members homozygous for the NPHS2 p.R229Q variant is presented: a 37-year-old patient who was diagnosed with proteinuria at age 7 months, focal segmental glomerulosclerosis (FSGS) at age 20 years, and end-stage renal disease (ESRD) at age 33 years, his59year-oldfatherandhis40year-oldbrother,bothunaffected with no proteinuria. The affected son also harbors a heterozygous de novo, truncating PAX2 mutation (c.76dupG, p.V26Gfs*28), which can explain his chronic renal failure but which is rarely associated with FSGS. Conclusions This family provides further evidence that homozygous p.R229Q in itself may not cause FSGS. Nevertheless, the rare association of FSGS to a PAX2 mutation may reflect the modifier effect of p.R229Q in the homozygous state. Such a modifier effect can also explain its enrichment in SRNS patients. Patients with homozygous p.R229Q should be screened for the causative mutation in a second gene. Keywords Nephrotic syndrome * NPHS2 * Pathogenicity * Podocin * PAX2
Background NPHS2, the gene encoding the slit diaphragm protein podocin, is the most frequently mutated gene in steroid-resistant nephrotic syndrome (SRNS) presenting in childhood and young adulthood [1-4]. Its mutations [...]