Autosomal Dominant Polycystic Kidney Disease

Preferred test for molecular confirmation of suspected clinical diagnosis of ADPKD

Acceptable test for molecular confirmation of suspected clinical diagnosis of ADPKD

Related Tests

Useful for confirming a diagnosis when a pathogenic sequence variant has been identified in a family member

  • A copy of the family member’s lab report documenting the familial variant is REQUIRED

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic condition that leads to the development of renal cysts and end-stage renal disease (ESRD) by the age of 60 years in 50% of affected individuals; it is the fourth leading cause of ESRD. ADPKD is caused by pathogenic variants in PKD1 or PKD2. Genetic testing can be used to confirm a diagnosis of ADPKD in those with a confirmed or suspected clinical diagnosis, especially for individuals with equivocal renal imaging results, or as predictive testing for younger at-risk individuals being evaluated as potential living related kidney donors. Presymptomatic testing in minors is not recommended.

Disease Overview

Prevalence

1/500-1,000 in the U.S. 

Age of onset: usually adult onset of symptoms

Symptoms

  • Kidneys
    • Bilateral renal cysts (may be present from birth)
    • Renal pain
    • Renal insufficiency (leading to hypertension)
    • Dilated renal tubules
    • Enlarged kidneys
    • ESRD
  • Connective tissue
    • Intracranial aneurysms and/or hemorrhaging
    • Dolichoectasia
    • Dilation of aortic root
    • Aortic dissections
    • Mitral valve prolapse
    • Abdominal wall hernias
  • Cysts may appear in other organs
    • Liver
    • Pancreas
    • Seminal vesicles
    • Arachnoid membrane

Diagnostic Criteria

Renal imaging can be used in at-risk individuals to identify renal cysts and diagnose ADPKD. The positive predictive value (PPV) of imaging is nearly 100% when following the Demetriou criteria below for at-risk individuals with a first-degree family member affected with ADPKD. 

Age (Yrs) Number of Cysts

15-39

>3 in 1 or 2 kidneys

40-59

>4, with ≥2 in each kidney

≥60

>8, with ≥4 in each kidney

Genetics

Genes

PKD1, PKD2 

Inheritance

  • Autosomal dominant
  • De novo rate: ~10% 

Penetrance

  • Penetrance is age and genotype dependent
  • Nearly all older adults develop multiple renal cysts
  • Average age of onset for ERSD 
    • Individuals with PKD1 variants: 54 years
    • Individuals with PKD2 variants: 74 years

Test Interpretation

Sensitivity/Specificity

  • Clinical sensitivity
    • Greater than 90% of individuals with ADPKD will have an identifiable variant in PKD1 or PKD2 
      • 85% of cases are attributed to variants in PKD1  
      • Variants in PKD1 are associated with more severe disease, including earlier age of diagnosis and onset of ESRD
      • 15% of cases are attributed to variants in PKD2  
    • Sequence variants account for majority of pathogenic variants (~97%) 
    • Large deletions/duplications in PKD1 or PKD2 account for a small percent of ADPKD cases (~3%) 
      • Large deletions involving PKD1/TSC2 result in contiguous gene deletion syndrome with early-onset PKD and features of tuberous sclerosis
  • Analytical sensitivity: 99%
  • Analytical specificity: 99%

Results

Results Variant(s) Detected Clinical Significance

Positive

At least 1pathogenic variant detected in PKD1 or PKD2

Confirms diagnosis of ADPKD

Negative

No pathogenic variants detected in either PKD1 or PKD2

Reduces the likelihood of, but does not exclude, a diagnosis of ADPKD

Inconclusive

Variant of unknown clinical significance

Unknown if disease causing or benign

Limitations

  • A negative result does not exclude a diagnosis of ADPKD
  • Not detected:
    • Large deletions/duplications in PKD1 (exons 1, 2, 4, 8, 17, 24, 28, 32, 34, and 45)
    • Regulatory region or deep intronic variants
  • Mosaic variants in PKD1 or PKD2 may not be detected
  • Breakpoints for large deletions/duplications will not be determined
  • Diagnostic errors can occur due to rare sequence variations

References