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
  • Useful for confirming a diagnosis when a pathogenic deletion/duplication variant has been identified in 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 1 pathogenic 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