Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification
Polymerase Chain Reaction/Sequencing
Acceptable test for molecular confirmation of suspected clinical diagnosis of ADPKD
Related Tests
Polymerase Chain Reaction/Sequencing
- 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
Multiplex Ligation-dependent Probe Amplification
- 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
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
Inheritance
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
- 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
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25186187
Paul BM, Vanden Heuvel GB. Kidney: polycystic kidney disease. Wiley Interdiscip Rev Dev Biol. 2014;3(6):465-487.
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Gradzik M, Niemczyk M, Gołębiowski M, et al. Diagnostic imaging of autosomal dominant polycystic kidney disease. Pol J Radiol. 2016;81:441-453.
PubMed -
GeneReviews - Autosomal dominant polycystic kidney disease
Harris PC, Torres VE. Polycystic kidney disease, autosomal dominant. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews, University of Washington; 1993-2020. [Last update: Jul 2018; Accessed: Sep 2020]
Online -
17582161
Rossetti S, Consugar MB, Chapman AB, et al. Comprehensive molecular diagnostics in autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2007;18(7):2143-2160.
PubMed -
18818683
Consugar MB, Wong WC, Lundquist PA, et al. Characterization of large rearrangements in autosomal dominant polycystic kidney disease and the PKD1/TSC2 contiguous gene syndrome. Kidney Int. 2008;74(11):1468-1479.
PubMed
Preferred test for molecular confirmation of suspected clinical diagnosis of ADPKD