What are the tests for PKD1 (Polycystic Kidney Disease 1) and PKD2 (Polycystic Kidney Disease 2)?

Genetic Testing for PKD1 and PKD2 in Polycystic Kidney Disease

The primary tests for detecting PKD1 and PKD2 mutations are next-generation sequencing (NGS) panels, which may include targeted gene sequencing, whole exome sequencing, or comprehensive multigene panels that cover polycystic kidney disease genes with protocols adequately covering the complex PKD1 gene structure. 1

Types of Genetic Tests Available for PKD1 and PKD2

Primary Testing Methods

• Next-Generation Sequencing (NGS) - The preferred method due to its ability to handle the complexity of PKD1 and PKD2 genes:
  • Targeted gene panels: Specifically designed to analyze PKD1 and PKD2 simultaneously 2, 3
  • Whole exome sequencing (WES): Sequences the entire exome with computational analysis focused on PKD genes 1
  • Multigene panels: Include PKD1, PKD2, and other cystic kidney disease genes 1

Confirmatory Testing

• Sanger sequencing: Used to confirm variants detected by NGS 4
• Multiplex ligation-dependent probe amplification (MLPA): Detects large deletions/duplications that NGS might miss 4

Technical Challenges in PKD1/PKD2 Testing

PKD1 testing presents unique challenges that require specialized techniques:

• PKD1 complexity: The gene has six pseudogenes that share 97% homology with exons 1-32 5
• Long-range PCR: Required to specifically amplify the PKD1 gene and distinguish it from pseudogenes 2, 3
• High genetic heterogeneity: Over 2,300 mutations reported for PKD1 and over 270 for PKD2 1

When Genetic Testing is Recommended

According to KDIGO and other guidelines, genetic testing is recommended in specific situations:

1. Diagnostic uncertainty: When renal imaging is inconclusive 1
2. Atypical presentation: Early and severe disease or discordant imaging/GFR 1
3. Negative family history: Potential de novo mutations 1
4. Living kidney donor evaluation: Young (aged <30 years) related donors at risk of ADPKD 1
5. Family planning: For reproductive counseling 1
6. Very-early-onset disease: Regardless of family history 1

Testing Algorithm

1. For patients with typical ADPKD and positive family history:

   • Imaging (ultrasound, MRI, or CT) is usually sufficient for diagnosis
   • Genetic testing only if needed for family planning or donor evaluation

2. For patients with atypical presentation or negative family history:

   • Start with a multigene panel that includes PKD1, PKD2, and other cystic kidney disease genes (PKHD1, HNF1B, GANAB, etc.) 1
   • Ensure the testing protocol adequately covers PKD1 with long-range PCR 1

3. For very-early-onset disease in children:

   • Use a comprehensive multigene panel regardless of family history 1

Clinical Utility and Limitations

• Diagnostic yield: Modern NGS-based testing can achieve 89-93% detection rates for pathogenic mutations 4
• Prognostic value: PKD1 mutations (especially truncating) generally cause more severe disease than PKD2 mutations 6
• Limitations:
  • Mosaicism may be missed if present at low levels
  • Some deep intronic variants may be missed
  • Variants of unknown significance may complicate interpretation

Important Caveats

• Genetic testing should be accompanied by genetic counseling before and after testing 1
• In clinical practice, ADPKD diagnosis is often based on imaging rather than genetic testing due to cost and insurance coverage issues 1
• The TSC2-PKD1 contiguous gene syndrome (deletion affecting both genes) should be considered in cases with early-onset polycystic kidney disease and features of tuberous sclerosis 1
• Genetic testing may identify mutations in genes other than PKD1/PKD2 that can mimic ADPKD, which has implications for prognosis and management 1

By understanding the appropriate testing methods and indications, clinicians can make informed decisions about when genetic testing for PKD1 and PKD2 will provide meaningful clinical benefit for patients with suspected ADPKD.