Test ID: WDKM
Wilson Disease Known Mutation, ATP7B DNA Sequencing

Diagnostic confirmation of Wilson disease when familial mutations have been previously identified

Carrier testing of individuals when a mutation in the ATP7B gene has been identified in an affected family member.

Documentation of the specific familial mutations must be provided with the specimen in order to perform this test.

• Molecular Genetics-Congenital Inherited Diseases Patient Information Sheet
• Informed Consent for Genetic Testing

Polymerase chain reaction (PCR)/DNA sequencing are utilized to test for the presence of a specific mutation previously identified in an affected family member.
(PCR is utilized pursuant to a license agreement with Roche Molecular Systems, Inc.)

This test can only be performed if a mutation has previously been identified in a family member of this individual.

Specimen must arrive within 96 hours of collection.

Specimen Type: Whole blood

Container/Tube:

Preferred: Lavender top (EDTA) or yellow top (ACD)

Acceptable: Any anticoagulant

Specimen Volume: 3 mL

Collection Instructions:

1. Invert several times to mix blood.

2. Send specimen in original tube.

Specimen Stability Information: Ambient (preferred)/Refrigerated

Forms:                                    

1. Molecular Genetics-Congenital Inherited Diseases Patient Information Sheet (Supply T521) in Special Instructions

2. New York Clients-Informed consent is required. Please document on the request form or electronic order that a copy is on file. An Informed Consent for Genetic Testing (Supply T576) is available in Special Instructions.          

3. If not ordering electronically, submit a Molecular Genetics Request Form (Supply T245) with the specimen.

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 >50% of identified disease alleles in the Northern European Caucasian population.

An interpretive report will be provided.

An interpretive report will be provided.

The identification of a disease-causing mutation in an affected family member is necessary before predictive testing for other family members can be offered. If a familial mutation has not been previously identified, order WDMS/83697 Wilson Disease Mutation Screen, ATP7B DNA Sequencing.

Analysis is performed for the familial mutations provided only. This assay does not rule out the presence of other mutations within this gene or within other genes that may be associated with Wilson disease.

Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Any error in the diagnosis or in the pedigree provided to us, including false-paternity, could lead to erroneous interpretation of results.

A previous bone marrow transplant from an allogenic donor will interfere with testing. Call Mayo Medical Laboratories for instructions for testing patients who have received a bone marrow transplant.

Ninety-six normal Caucasian samples were screened for the presence of benign polymorphisms in the ATP7B gene. Selected exons from 21 of these specimens were confirmed by direct sequencing to have at least a single polymorphism. One normal sample was found to be a carrier of an ATP7B mutation (IVS11-2A->G). Five WD patients with known ATP7B mutations were sequenced with 100% concordance.

1. 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

2. Mak CM, Lam CW: Diagnosis of Wilson's disease: a comprehensive review. Crit Rev Clin Lab Sci 2008;45(3):263-290

DNA sequence analysis is utilized to test for the presence of a specific mutation(s) previously identified in an affected family member. (Gu YH, Kodama H, Du SL, et al: Mutation spectrum and polymorphisms in ATP7B identified on direct sequencing of all exons in Chinese Han and Hui ethnic patients with Wilson's disease. Clin Genet 2003 Dec;64[6]:479-484)

Friday; 10 a.m.

81403-Known familial variant not otherwise specified, for gene listed in Tier 1 or Tier 2, DNA sequence analysis, each variant exon