Wilson Disease (ATP7B) Sequencing

Biochemical and/or genetic testing may be used in evaluating individual for WD.

  • Biochemical testing is more cost effective.
  • Genetic testing has higher sensitivity and specificity.
  • Combination of both is useful for diagnosis

Preferred test for genetic confirmation of Wilson disease or determination of carrier status

Related Tests

May be used as initial screening test in WD or copper transport disorders

Useful in the assessment of deficiency or overload

  • May be useful in the assessment of overload or response to copper-reducing therapies
  • Directly measures the free (nonceruloplasmin bound) fraction of copper

Useful in the assessment of overload

Useful in the assessment of overload

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

98% 

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

Additional Resources