SickKids

Paediatric Laboratory Medicine
Paediatric Laboratory Medicine
print        

Focal Segmental Glomerulosclerosis

Background
Who should be tested?
Testing Methodology
Potential Outcomes & Interpretation of Test Results
Cautions
For More Information

Background

Focal segmental glomerulosclerosis (FSGS) is a histopathologic finding in nephrotic syndrome in children and adults characterized by; excessive urine protein excretion (proteinuria), generalized or isolated swelling of the body tissues (edema), decreased blood protein levels (hypoalbuminemia), and elevated blood lipid levels (hyperlipidemia). FSGS frequently leads to progression to end-stage renal disease (ESRD), requiring renal replacement therapy in the form of dialysis or kidney transplantation.

FSGS can be either primary, due to genetic mutations or secondary, the result of other conditions. The primary form, genetic in origin, has been observed in both sporadic cases and in patients with a family history of FSGS. FSGS is associated with both an autosomal recessive (AR) and autosomal dominant (AD) pattern of inheritance. The four genes primarily involved in FSGS are: NPHS2, on chromsome 1 which encodes the protein podocin; ACTN4, located on chromsome 19 which encodes the protein actinin; TRPC6, located on chromsome 11 which encodes the protein transient receptor potential (TRP); and CD2AP on chromosome 6 which encodes the protein CD2-associated protein. Approximately 50% of FSGS patients will have mutations in the NPHS2, TRPC6, ACTN4 or CD2AP gene. Molecular testing for FSGS consists of complete sequencing of the coding region and flanking exon/intron boundaries of the four genes listed above to detect point mutations.

The autosomal recessive (AR) form of FSGS is present when a child receives two copies of a defective NPHS2 gene, one from each parent. Any person with one copy of the defective NPHS2 gene is a carrier. Carriers do not have, and will not develop, FSGS. However, if two carriers wish to have children, there is a one in four chance (25%) that their baby will develop FSGS. There is a three in four chance (75%) that their baby will not have AR FSGS. The autosomal dominant (AD) form of FSGS is present when an individual has one copy of the defective TRPC6 or ACTN4 gene. Affected individuals have a 50% chance of transmitting the disorder to each child. There is a 50% chance that the affected individual’s offspring will not be affected with FSGS. Mutations in CD2AP have been reported showing both autosomal recessive and autosomal dominant inheritance patterns

Who should be tested

  • individuals clinically suspected of being affected with FSGS
  • individuals with a family history of FSGS, to determine the carrier status of unaffected individuals
  • pregnancies at increased risk of being affected with FSGS

Testing Methodology

Direct Mutation Analysis: Direct sequencing to identify point mutations in the NPHS2, TRPC6, ACTN4 and CD2AP genes

Sensitivity of the Test: Approximately 50% of FSGS patients will have mutations in either the NPHS2, TRPC6, ACTN4 or CD2AP gene.

Note: Sequence changes detected by these tests may be interpreted as disease causing mutations because they will clearly disrupt the protein or have been previously associated with the disease. Other sequence changes may be interpreted as benign polymorphisms because they have been detected in unaffected individuals. However in some patients a change in the gene sequence may be detected but the laboratory may not be able to determine if this change causes disease because it is not clear that the sequence affects protein function, the change has not previously been reported in the literature to cause disease nor been described as a benign polymorphism. These “variants of unknown significance” could potentially be a disease causing mutation or could be benign polymorphism and should be interpreted in the context of clinical findings, family history and other experimental data

Potential Outcomes & Interpretation of Test Results

Reason for referral

Gene Mutations
allele 1 / allele 2

Explanation

diagnosis

none detected / none detected

  • This result does not support a diagnosis of FSGS

diagnosis

mutation detected / none detected

  • This result supports a diagnosis of FSGS.
    (mutation in TRPC6/ACTN4/CD2AP).

diagnosis

mutation detected / none detected

  • This result supports a diagnosis of FSGS (mutation in CD2AP/NPHS2)

 

 

 

presymptomatic testing

none detected / none detected

  • This individual is unlikely to develop FSGS since the family mutation in TRPC6/ACTN4/CD2AP is not identified

presymptomatic testing

mutation detected / none detected

  • This individual has a TRPC6/ACTN4/CD2AP mutation, and may develop FSGS and transmit a mutation to offspring.

carrier testing

mutation detected / none detected

  • This individual has a NPHS2/CD2AP mutation, and may transmit a mutation to offspring.

Cautions

  • Current molecular testing will not detect all possible mutations in this gene. A negative result does not rule out the possibility that the individual carries a rare NPHS2, TRPC6, ACTN4 or CD2AP gene mutation not detected by this assay.
  • The clinical course or severity of symptoms cannot be predicted by molecular analysis.
  • Test results should be interpreted in the context of clinical findings, family history, ethnic background and other laboratory data.
  • This test was developed and its performance characteristics validated by the Molecular Genetics Laboratory at the Hospital for Sick Children. It has not been cleared or approved by the U.S. Food and Drug Administration. The FDA has determined that such clearance or approval is not necessary. This test is used for clinical purposes.

For More Information