Characteristics of the test: (includes 3 genes)

NPHS1 (OMIM # 602716)

NPHS2 (OMIM # 604766)

WT1 (OMIM # 607102)

General characteristics of the clinical phenotype

The nephrotic syndromes are characterised with massive proteinuria, hypoalbuminuria and oedema. This is a heterogeneous group of disorders resulting from impaired function of the podocytes in the glomeruli and increased penetrance of the renal filter. In children, several histological sub-types of the disease can be distinguished such as minimal-change nephropathy, focal segmental glomerulosclerosis and diffuse mesangial proliferative glomerulonephritis. It has been found that the response to corticoid treatment rather than the histological characteristics of each patient have better prognostic value for the disease progression. Thus, nephrotic syndromes are often classified as steroid-sensitive (SSNS, quick resolution of the proteinuria following initiation of therapy) and steroid-resistant (SRNS, treatment is not associated with remission). In rare cases SRNS is associated with anomalies of the development of the genitourinary tract and/or Wilms’ tumours (Denys-Drash OMIM #194080 and Fraser OMIM # 136680 syndromes; neprhoblastoma or Wilms’ tumour OMIM # 194070).

The steroid-resistant form of the disease is diagnosed in app. 10% of the nephrotic syndrome patients and is associated with increased risk of complications. Most of the cases are due to genetic mutations, with the NPHS1, NPHS2 and WT1 genes being affected in a substantial number of patients. Mutations in the NPHS1 and NPHS2 genes are associated with an autosomal recessive form of the diseases, i.e. disease develops only if both copies of the gene are affected. On the other hand, pathogenic variants in WT1 are dominant, i.e. presence of one affected copy is sufficient for clinical presentation of the disease.

Mutation screening of these 3 genes allows identification of the molecular cause of the disease in app. 25% of the SRNS patients,

Reasons for referring: 

Patients with steroid-resistant nephrotic syndrome, without developmental anomalies of the genitourinary tract or Wilms’ tumours.

Interpretation of results:

• Identification of point mutations and small deletions/insertions in NPHS1, NPHS2 and WT1 will lead to genetic diagnosis and will help the clinical team to choose the best suited treatment for you or your child;

• The presence of WT1 mutations is associated with increased risk for Wilms’ tumours – solid tumours of the kidney that appear in childhood. Routine prophylaxis in these cases will ensure early diagnoses and successful therapy of this condition. 

• Our genetic counsellor will interpret the result for you and will answer any questions you may have.

Method: Sanger sequencing (ABI 3130xl).

The method involves bidirectional DNA sequencing of all coding exons and intron-exon boundaries of the NPHS1 и NPHS2, as well as exons 8 and 9 of the WT1 gene.

For patients with SRNS accompanied with developmental anomalies in the genitourinary tract and/or nephroblastoma, sequencing of all WT1 exons is recommended. In those cases screening for NPHS1 and NPHS2 mutations may not be necessary. 

The laboratory offers single exon sequencing for establishing the carrier status of close relatives of patients with known NPHS1, NPHS2 or WT1 mutations. 

Sensitivity of the method: 99.5%

What does the test involve? 

• DNA isolation and sample storage.

• Direct sequencing of target genes / gene regions to detect pathogenic mutations.

• Preparation of written result from the genetic test.

• Diagnostic interpretation of the results and genetic counselling.

Biological material: Venous blood of DNA

For more information, please read "Biological Sample Requirements and Transport Information" carefully.