A small percentage of individuals who are carriers or have a diagnosis of Wilson disease (WD) may have a mutation that is not identified by this method (eg, large genomic deletions, promoter mutations, deep intronic mutations). The absence of a mutation, therefore, does not eliminate the possibility of positive carrier status or the diagnosis of WD. For carrier testing, it is important to first document the presence of an ATP7B gene mutation in an affected family member.
Test results should be interpreted in context of clinical findings, family history, and other laboratory data. Misinterpretation of results may occur if the information provided is inaccurate or incomplete.
In some cases, DNA variants of undetermined significance may be identified.
Due to the limitations of next-generation sequencing, small deletions and insertions may not be detected by this test. If a diagnosis is still suspected, contact a molecular genetic counselor in the Genomics Laboratory at 800-533-1710 for more information regarding follow-up testing options.
Rare polymorphisms exist that could lead to false-negative or false-positive results. If results obtained do not match the clinical findings, additional testing should be considered.
Multiple in-silico evaluation tools were used to assist in the interpretation of these results. These tools are updated regularly; therefore changes to these algorithms may result in different predictions for a given alteration. Additionally, the predictability of these tools for the determination of pathogenicity is currently unvalidated.
Unless reported or predicted to cause disease, alterations that do not result in an amino acid substitution are not reported.
Reclassification of Variants-Policy:
All detected alterations are evaluated according to American College of Medical Genetics and Genomics (ACMG) recommendations. Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance. At this time, it is not standard practice for the laboratory to systematically review likely pathogenic alterations or variants of uncertain significance that are detected and reported. The laboratory encourages health care providers to contact the laboratory at any time to learn how the status of a particular variant may have changed over time.
Wilson disease (WD) is an autosomal recessive disorder that results from the body's inability to excrete excess copper. Typically, the liver releases excess copper into the bile. Individuals with WD lack the necessary enzyme that facilitates clearance of copper from the liver to bile. As a result, copper accumulates first in the liver and gradually in other organs. The brain, kidneys, bones, and corneas can also be affected. WD affects approximately 1 in 30,000 people worldwide, with a carrier frequency of approximately 1 in 90 individuals.
The primary clinical manifestations of WD are hepatic and neurologic. Hepatic disease can be quite variable, ranging from hepatomegaly or other nonspecific symptoms that mimic viral hepatitis to severe liver damage, such as cirrhosis. Neurologic symptoms of WD can include poor fine-motor coordination, ataxia, and dysphagia. Psychiatric manifestations are reported in approximately 20% of individuals with WD. A characteristic ophthalmologic finding is the Kayser-Fleischer ring. Individuals with WD typically begin to show symptoms of liver dysfunction or neurologic disease in the first or second decade of life. If not treated, WD can cause liver failure, severe brain damage, and even death.
A variety of laboratory tests are recommended in the initial evaluation for WD. In approximately 95% of cases, serum ceruloplasmin is below normal. Additionally, patients with WD show decreased copper in serum, increased copper in urine, and significantly elevated copper on liver biopsy. While liver biopsy is not recommended as a first-tier screening test for WD, it can be useful to help interpret discrepant biochemical or molecular results. The other tests should be performed prior to sequence analysis of the ATP7B gene, the gene responsible for WD. More than 300 disease-causing mutations have been identified in the ATP7B gene. Most mutations are family-specific with the exception of the H1069Q mutation, which accounts for greater than 50% of identified disease alleles in the Northern European Caucasian population.