Abstract
Mutations in the gene encoding podocin (NPHS2) cause autosomal recessive steroid-resistant nephrotic syndrome (SRNS). For addressing the possibility of a genotype-phenotype correlation between podocin mutations and age of onset, a worldwide cohort of 430 patients from 404 different families with SRNS were screened by direct sequencing. Recessive podocin mutations were present in 18.1% (73 of 404) of families with SRNS, and 69.9% of these mutations were nonsense, frameshift, or homozygous R138Q. Patients with these mutations manifested symptoms at a significantly earlier age (mean onset <1.75 years) than any other patient group, with or without podocin mutations, in this study (mean onset >4.17 yr). All but one patient affected by truncating or homozygous R138Q mutations developed SRNS before 6 yr of age. Patient groups with other recessive podocin mutations, with single heterozygous podocin mutations, with sequence variants, and with no podocin changes could not be distinguished from each other on the basis of age of onset. In conclusion, nephrotic syndrome in children with truncating or homozygous R138Q mutations manifests predominantly before 6 yr of life, and the onset of disease is significantly earlier than for any other podocin mutations. Because the age of onset can vary by several years among those with identical mutations, additional factors may modify the phenotype.