ABSTRACT
Mutations of NPHS2, encoding podocin, are the main cause of autosomal recessive steroid-resistant nephrotic syndrome (NS) presenting in childhood. Adult-onset steroid-resistant NS has been described in patients heterozygous for a pathogenic NPHS2 mutation together with the p.R229Q variant. To determine the frequency and the phenotype of patients carrying the p.R229Q variant, we sequenced the complete coding region of NPHS2 in 455 families (546 patients) non-responsive to immunosuppressive therapy or without relapse after transplantation. Among affected Europeans, the p.R229Q allele was significantly more frequent compared to control individuals. Thirty-six patients from 27 families (11 families from Europe and 14 from South America) were compound heterozygotes for the p.R229Q variant and one pathogenic mutation. These patients had significantly later onset of NS and end stage renal disease than patients with two pathogenic mutations. Among 119 patients diagnosed with NS presenting after 18 years of age, 18 patients were found to have one pathogenic mutation and p.R229Q, but none had two pathogenic mutations. Our study shows that compound heterozygosity for p.R229Q is associated with adult-onset steroid-resistant NS, mostly among patients of European and South American origin. Screening for the p.R229Q variant is recommended in these patients along with further NPHS2 mutation analysis in those carrying the variant.