Congenital nephrotic syndrome of the Finnish type (CNF) is an autosomal recessive disease characterized by massive proteinuria, sometimes beginning in utero. Most patients progress to end stage renal disease (ESRD) within two to three years. The genetic basis of CNF was elucidated in 1998 with the cloning of the NPHS1 gene¹. The majority of Finnish patients with CNF have one of two common mutations, but mutations have been identified throughout the gene, and in many different populations². Recently, a high alpha-fetoprotein (AFP) level, which is a commonly used marker for CNF, has been shown to be an unreliable marker for CNF³. In addition, recent discoveries suggest NPHS2 mutations may play a role in CNF pathogenesis, and that patients with mutations in both NPHS1 and NPHS2 have a unique phenotype, distinct from both CNF and steroid-resistant nephrotic syndrome, the phenotype historically associated with NPHS2 mutations⁴.

Athena is pleased to offer bi-directional sequencing of the coding region of the NPHS1 gene to assist in the diagnosis of CNF. Order NPHS1 (Nephrin) Sequencing Analysis (Unit Code 730). Also available for enhanced diagnostic accuracy is sequencing of the coding regions of both the NPHS1 and NPHS2 genes with Athena’s Nephrotic Syndrome Evaluation (Unit Code 720).

Indications for Testing

• Congenital nephrotic syndrome of the Finnish type (proband)
• Congenital nephrotic syndrome of the Finnish type (family testing)
• Atypical CNF
• In place of elevated AFP for diagnosis of CNF
• Congenital FSGS
• Late-onset FSGS

Congenital Nephrotic Syndrome and Focal Segmental Glomerulosclerosis

Alterations of the NPHS1 gene have been shown to be associated with congenital nephrotic syndrome of the Finnish type (CNF)¹. Recent evidence suggests that NPHS1 alterations can also be associated with congenital or late-onset focal segmental glomerulosclerosis (FSGS), when found in combination with NPHS2 alterations.

While most CNF patients described to date have mutations in NPHS1, recently published results⁴ show that NPHS2 mutations can be associated with both CNF and congenital FSGS. In this study, 12 of the 41 CNF patients examined (29.3%) had NPHS2 mutations either in combination with or in the absence of NPHS1 mutations. Of the 8 patients with NPHS2 mutations and no NPHS1 mutations, two had a severe CNF phenotype. All four patients with both NPHS1 and NPHS2 mutations had a congenital FSGS phenotype.

The authors state “These findings…emphasise the importance of screening for both NPHS1 and NPHS2 mutations in CNF, especially when no NPHS1 mutation is apparent.” They go on to say that “…a diagnosis of CNF can result from both NPHS1 and NPHS2 mutations, and that a molecular diagnosis of congenital nephrotic syndrome should incorporate mutational analysis of both genes.”

In a separate study⁵, NPHS2 mutations were associated with a late-onset FSGS, and a previously reported polymorphism (R229Q) that is common in the general population was shown to be associated with FSGS when found with other NPHS2 mutations. In this important paper, NPHS2 mutations were found in 9 of 30 (30%) families with recessive FSGS.

Sequencing of the NPHS1 gene may also be important in cases that do not present as typical CNF. Indeed, Lenkkeri, et al⁶ conclude that “…mutations in nephrin may be involved in proteinuric patients who do not exhibit the classic severe Finnish type of CNF. Consequently, there is a reason to examine the involvement of nephrin in both genetic and acquired kidney disorders in which proteinuria is displayed.”

Elevated alpha-fetoprotein (AFP)

In addition to confirmatory testing in probands, prenatal testing can be extremely important in subsequent pregnancies. Clinical diagnosis of CNF in the proband is often straightforward. However, many couples who have had one child with CNF wish to have additional children. Because CNF is inherited in an autosomal recessive pattern, this presents an obvious risk of having a second child with the condition.

Often, in pregnancies following the birth of a child with CNF, enlarged placenta, proteinuria in utero and high AFP levels are used as clinical markers for prenatal counseling. However, a recent study that retrospectively examined 21 pregnancies, which had been terminated due to elevated AFP levels, indicates that this method can lead to false positive results³. The authors retrospectively examined 21 fetuses that had been terminated due to high AFP levels following an affected birth or associated with positive family history for CNF. They discovered that 12 of the 21 were homozygous for either the Fin_major or Fin_minor mutations, but the remaining 9 (43%) were carriers for either the Fin_major or Fin_minor mutations. This study highlights the risk of making a termination decision based on elevated AFP and positive family history, arguing in favor of molecular testing in these cases.

REFERENCES

1. Kestila, M., et al., (1998) Positionally cloned gene for a novel glomerular protein – nephrin – is mutated in congenital nephrotic syndrome. Molec. Cell 1:575-582.
2. Beltcheva, O., et al., (2001) Mutation spectrum in the nephrin gene (NPHS1) in congenital nephrotic syndrome. Hum. Mutation 17:368-373.
3. Patrakka. J., et al., (2002) Proteinuria and prenatal diagnosis of congenital nephrosis in fetal carriers of nephrin gene mutations. Lancet 359:1575-1577.
4. Koziell, A., et al., (2002) Genotype/phenotype correlations of NPHS1 and NPHS2 mutations in nephrotic syndrome advocate a functional inter-relationship in glomerular filtration. Hum. Molec. Genet. 11(4):379-388.
5. Tsukaguchi, H., et al., (2002) NPHS2 mutations in late-onset focal segmental glomerulosclerosis: R229Q is a common disease-associated allele. J. Clin. Investigation 110(11):1659-1666.
6. Lenkkeri, U., et al. (1999) Structure of the gene for congenital nephrotic syndrome of the Finnish type (NPHS1) and characterization of mutations. Am. J. Hum. Genet. 64:51-61.