FeedbackMassively Parallel Sequencing
Preferred test for genetic confirmation of Wilson disease or determination of carrier status
Related Tests
Quantitative Immunoturbidimetry
May be used as initial screening test in WD or copper transport disorders
Quantitative Inductively Coupled Plasma-Mass Spectrometry
Useful in the assessment of deficiency or overload
Quantitative Inductively Coupled Plasma-Mass Spectrometry (ICP-MS)
- May be useful in the assessment of overload or response to copper-reducing therapies
- Directly measures the free (nonceruloplasmin bound) fraction of copper
Quantitative Inductively Coupled Plasma-Mass Spectrometry
Useful in the assessment of overload
Quantitative Inductively Coupled Plasma-Mass Spectrometry
Useful in the assessment of overload
Quantitative Inductively Coupled Plasma-Mass Spectrometry
May be useful when related serum or urine assessments are inconclusive
Wilson disease (WD) is a rare inherited genetic disorder caused by pathogenic variants in the ATP7B gene, resulting in excessive amounts of copper accumulating in the body, particularly in the liver, brain, and eyes. Signs and symptoms most often appear during the teens but may appear as early as age 6 or as late as the mid-40s. Liver disease is typically the initial feature of Wilson disease in affected children and young adults. Nervous system or psychiatric problems are often the initial features in individuals diagnosed in adulthood, and commonly occur in young adults. Neurologic symptoms include clumsiness, tremors, difficulty walking, and speech problems. Psychiatric symptoms include impaired thinking, depression, anxiety, and mood swings. Individuals with Wilson disease may have copper deposits in the cornea that form a green to brown ring around the iris (Kayser-Fleischer ring). These individuals may demonstrate abnormalities in eye movement, such as the inability to look upward.
Disease Overview
Diagnosis
- Slit-lamp examination of cornea to detect Kayser-Fleischer rings
- Combination of biochemical findings:
- Serum ceruloplasmin: low
- Serum copper: low
- Free copper: high
- 24-hour urine copper: elevated
- Hepatic copper concentration on liver biopsy: elevated
- Testing ATP7B gene for variants can confirm diagnosis
- Most reliable method of diagnosis
- Can help determine if individual is presymptomatic or an unaffected carrier
Diagnostic Issues
- Affected individuals occasionally have normal biochemical test results
- Up to 20% of WD carriers have equivocal biochemical findings
Treatment
- Disease is fatal if untreated
- Treatment includes use of chelating agents to prevent or reverse symptoms
- Only cure is liver transplant
Genetics
Gene
ATP7B
Inheritance
Autosomal recessive
Penetrance
Age dependent, may be reduced
Test Interpretation
Clinical Sensitivity
Analytical Sensitivity
For massively parallel sequencing:
| Variant Class | Analytical Sensitivity (PPA) Estimatea (%) | Analytical Sensitivity (PPA) 95% Credibility Regiona (%) |
|---|---|---|
|
SNVs |
>99 |
96.9-99.4 |
|
Deletions 1-10 bp |
93.8 |
84.3-98.2 |
|
Deletions 11-44 bp |
>99 |
87.8-100 |
|
Insertions 1-10 bp |
94.8 |
86.8-98.5 |
|
Insertions 11-23 bp |
>99 |
62.1-100 |
|
aGene included on this test is a subset of a larger methods-based validation from which the PPA values are derived. bp, base pairs; PPA, positive percent agreement; SNVs, single nucleotide variants |
||
Results
| Results as Reported in Patient Chart | Variant(s) Detected | Clinical Significance |
|---|---|---|
|
Positive |
Two pathogenic ATP7B gene variants detected on opposite chromosomes |
Consistent with a diagnosis of WD |
|
Negative |
No pathogenic ATP7B variants detected |
Significantly reduces the likelihood of being affected with or a carrier of WD |
|
See note |
One pathogenic ATP7B gene variant detected |
Individual is at least a carrier of WD and may be affected with WD if an undetected variant is present on the opposite chromosome |
|
Variants of uncertain clinical significance may be identified |
Uncertain |
Limitations
- Diagnostic errors can occur due to rare sequence variations
- Not determined or evaluated:
- Regulatory region variants, including the Sardinian founder variant, c.-436_-422del15
- Deep intronic variants
- Large deletions/duplications
- Variants in genes other than ATP7B
References
-
Patients with Wilson disease without detectable ATP7B mutations
Stättermayer A, Zoller HM, Weiss KH, et al. Patients with Wilson disease without detectable ATP7B mutations. Abstract 464. Boston, MA: 65th Annual Meeting of the American Association for the Study of Liver Diseases. 2014.
23518715
Coffey AJ, Durkie M, Hague S, et al. A genetic study of Wilson's disease in the United Kingdom. Brain. 2013;136(Pt 5):1476-1487.
18506894
Roberts EA, Schilsky ML, American Association for Study of Liver Diseases (AASLD). Diagnosis and treatment of Wilson disease: an update. Hepatology. 2008;47(6):2089-2111.
29341979
Socha P, Janczyk W, Dhawan A, et al. Wilson's disease in children: a position paper by the Hepatology Committee of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. 2018;66(2):334-344.
GeneReviews - Wilson Disease
Weiss KH. Wilson disease. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews, University of Washington; 1993-2020. [Last update: Jul 2016; Accessed: Aug 2021]
Biochemical and/or genetic testing may be used in evaluating individual for WD.