Genotype-phenotype correlations in non-Finnish congenital nephrotic syndrome

Abstract

Mutations in NPHS1, which encodes nephrin, are the main causes of congenital nephrotic syndrome (CNS) in Finnish patients, whereas mutations in NPHS2, which encodes podocin, are typically responsible for childhood-onset steroid-resistant nephrotic syndrome in European populations. Genotype-phenotype correlations are not well understood in non-Finnish patients. We evaluated the clinical presentation, kidney histology, and disease progression in non-Finnish CNS cases by mutational screening in 107 families (117 cases) by sequencing the entire coding regions of NPHS1, NPHS2, PLCE1, WT1, LAMB2, PDSS2, COQ2, and NEPH1. We found that CNS describes a heterogeneous group of disorders in non-Finnish populations. We identified nephrin and podocin mutations in most families and only rarely found mutations in genes implicated in other hereditary forms of NS. In approximately 20% of cases, we could not identify the underlying genetic cause. Consistent with the major role of nephrin at the slit diaphragm, NPHS1 mutations associated with an earlier onset of disease and worse renal outcomes than NPHS2 mutations. Milder cases resulting from mutant NPHS1 had either two mutations in the cytoplasmic tail or two missense mutations in the extracellular domain, including at least one that preserved structure and function. In addition, we extend the spectrum of known NPHS1 mutations by describing long NPHS1 deletions. In summary, these data demonstrate that CNS is not a distinct clinical entity in non-Finnish populations but rather a clinically and genetically heterogeneous group of disorders.

Figure 1.

Kidney survival is greater in patients with podocin mutations compared with nephrin gene mutations. Kaplan-Meier survival curve shows the proportion of patients who had NPHS1 or NPHS2 mutations and remain free of ESRD. We excluded patients who underwent preemptive nephrectomy, patients with mutations in other genes, and patients in whom mutations were not identified from the analysis. Red line, patients with NPHS2 mutations; blue line, patients with mutations in NPHS1. Kidney survival was significantly better among patients with NPHS2 mutations (time to reach ESRD 79 versus 32 months, NPHS2 versus NPHS1; Wilcoxon test P = 0.007).

Figure 2.

Female patients with mutations in the NPHS1 gene seem to show improved kidney survival compared to male patients. Kaplan-Meier survival curve shows the proportion of male and female patients who had mutations in NPHS1 and remained free of ESRD. We excluded from the analysis patients who underwent preemptive nephrectomy. Red line, female patients with NPHS1 mutations; blue line, male patients with NPHS1 mutations. There is a trend toward better kidney survival among female patients (time to reach ESRD 21 versus 40 months, female versus male patients; Wilcoxon test P = 0.07).