Gene test interpretation: ATP7B (Wilson disease gene)

INTRODUCTION — This monograph summarizes the interpretation of genetic testing for ATP7B, the main gene associated with Wilson disease. It does not discuss indications for testing and is not intended to replace clinical judgment in the decision to test or in the care of the tested person. These subjects are discussed separately [1].

OVERVIEW

How to read the report — The checklist provides important caveats for genetic testing (table 1). Any result obtained for research or by direct-to-consumer testing that has clinical implications for the tested individual or their relatives should be repeated in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory or comparable accreditation body in other jurisdictions, with verified patient identification.

Genetics — Wilson disease is an autosomal recessive disorder and is the result of pathogenic variants in ATP7B, a gene encoding a copper transport protein, ATP7B, on chromosome 13. ATP7B is a P-type ATPase expressed mainly in the liver and present in some other tissues at lower amounts. ATP7B binds copper at its N-terminal domain and is responsible for the transmembrane transport of copper using ATP as an energy source. (See "Wilson disease: Epidemiology and pathogenesis", section on 'Copper metabolism'.)

Biallelic, pathogenic (disease-causing) variants affecting both ATP7B alleles are required to develop Wilson disease. Typically, one pathogenic variant is inherited from each parent. Over 500 different pathogenic variants in the ATP7B gene have been identified in patients with Wilson disease. The p.His1069Gln (p.H1069Q) variant is one of the most common pathogenic variants, with an allelic frequency of 10 to 40 percent (30 to 70 percent among individuals from Central, Eastern, and Northern Europe). Most patients are compound heterozygotes, carrying different pathogenic variants on each copy of chromosome 13. (See "Wilson disease: Epidemiology and pathogenesis", section on 'Genetic defect in Wilson disease'.)

Disease associations — The clinical manifestations of Wilson disease are predominantly hepatic, neurologic, and psychiatric, with many patients having a combination of symptoms as a consequence of copper accumulation [2]

Hepatic disease — The liver is the initial site of copper accumulation in patients with Wilson disease. Hepatic manifestations range from asymptomatic biochemical abnormalities, often with steatosis, to acute hepatitis and acute liver failure (with an associated Coombs-negative hemolytic anemia), chronic hepatitis, and cirrhosis. In most patients some degree of liver disease, even if only histologic change, is usually present at the time Wilson disease is diagnosed. However, there is an increasing number of individuals diagnosed by molecular genetic testing at a very young age (less than three years of age) where there may not be any histologic change present.

The signs, symptoms, laboratory findings, and imaging findings in patients with hepatic Wilson disease vary with the degree of liver damage. (See "Wilson disease: Clinical manifestations, diagnosis, and natural history", section on 'Liver disease'.)

Signs and symptoms of hepatic Wilson disease include:

●Abdominal pain

●Jaundice

●Hepatomegaly

●Splenomegaly

●Ascites

●Upper gastrointestinal bleeding

●Stigmata of chronic liver disease

●Mental status changes due to hepatic encephalopathy

Neurologic manifestations — Neurologic manifestations of Wilson disease include dysarthria, dystonia, tremor, gait abnormalities/ataxia, parkinsonism, and drooling. Initially, only one symptom may be present, but as the disease progresses, complex combinations of neurologic signs and symptoms may develop. Patients with neurologic manifestations may have concurrent hepatic disease. (See "Wilson disease: Clinical manifestations, diagnosis, and natural history", section on 'Neurologic involvement'.)

Behavioral and psychiatric symptoms — Behavioral and psychiatric symptoms are more common in patients with neurologic involvement than in patients with hepatic involvement. Symptoms include depression (reported in 20 to 30 percent of patients with Wilson disease), personality change, incongruous behavior, and irritability. (See "Wilson disease: Clinical manifestations, diagnosis, and natural history", section on 'Psychiatric symptoms'.)

Hemolysis — Infrequently, Coombs-negative hemolytic anemia may be the initial symptom of Wilson disease; hemolysis occurs episodically. Hemolysis is not uniformly associated with acute liver failure but often occurs concurrently. (See "Wilson disease: Clinical manifestations, diagnosis, and natural history", section on 'Hemolysis'.)

Ocular manifestations — Kayser-Fleischer rings are brownish rings seen on slit lamp examination that are due to fine, pigmented, granular deposits of copper in Descemet's membrane in the cornea.

Kayser-Fleisher rings are thought to indicate copper within the central nervous system, and they dissipate over time with treatment directed towards the removal of copper. Kayser-Fleischer rings are a characteristic feature of Wilson disease; they are seen in approximately 98 percent of patients with neurologic manifestations but only 50 percent of patients with hepatic-only manifestations.

Sunflower cataracts are another ocular manifestation of Wilson disease that occur when copper accumulates in the lens. (See "Wilson disease: Clinical manifestations, diagnosis, and natural history", section on 'Ocular involvement'.)

Other manifestations — Wilson disease can also cause abnormalities related to copper deposition in other organs. (See "Wilson disease: Clinical manifestations, diagnosis, and natural history", section on 'Other organs'.)

MANAGEMENT — Patients with Wilson disease require lifelong therapy. Discontinuation of therapy can lead to disease progression with development of acute liver failure or other symptoms related to copper deposition. Treatment should be conceptualized as being given in two phases: initial therapy to stabilize the patient by removing tissue copper that has accumulated and then preventing reaccumulation (maintenance) (algorithm 1) [2].

Dietary measures — During the initial phase of treatment, patients should avoid consuming food with high copper content, in particular shellfish, nuts, chocolate, mushrooms, soy products, and organ meats. Dietary restriction is insufficient as sole therapy for Wilson disease. (See "Wilson disease: Management", section on 'General measures'.)

Treating copper overload

Asymptomatic patients — In asymptomatic patients, we recommend treatment with a chelating agent (eg, D-penicillamine or trientine). Zinc may be used in patients who lack organ damage and are reluctant to use or cannot tolerate a chelating agent. During initial treatment with zinc, liver biochemical tests should be monitored at least every four months and a chelating agent considered as an alternative or in conjunction with zinc if transaminases show signs of disease worsening. (See "Wilson disease: Management", section on 'Drug dosing and administration'.)

Symptomatic patients — Symptomatic patients should be treated with a chelating agent until stable. Patients typically require 6 to 18 months of higher-dose treatment, after which, if they demonstrate improvement and disease stabilization, they can be transitioned to maintenance therapy with lower doses of a chelator or with zinc.

Liver transplantation may be needed for patients who present with acute liver failure and in those with decompensated liver disease unresponsive to drug therapy. Liver transplantation for neurologic complications remains controversial.

Monitoring on therapy — Patients with Wilson disease require careful monitoring while on treatment. (See "Wilson disease: Management", section on 'Drug dosing and administration'.)

Other important considerations

Reproductive counseling — Preconception counseling is appropriate for individuals with Wilson disease (homozygous or compound heterozygous for pathogenic or likely pathogenic variants in ATP7B) who are considering childbearing. Partners of individuals with Wilson disease and partners of carriers (heterozygotes) may elect to undergo genetic testing to determine if any pathogenic or likely pathogenic variants in ATP7B are present that would confer a risk of Wilson disease in offspring, with the recognition that not all variants of ATP7B leading to disease have been identified. If there is a risk for Wilson disease, some may elect to conceive using donor gametes or in vitro fertilization (IVF) with preimplantation genetic testing (PGT). Testing is also available during a pregnancy or after birth.

Pregnancy appears to be safe in patients on D-penicillamine or trientine, but the dose is reduced to approximately 30 to 50 percent of the prepregnancy dose during the first trimester and until delivery, since these drugs are known to be teratogenic in animal models and higher doses may impair maternal wound healing should a cesarean section or episiotomy be required. Those patients on zinc treatment should continue it throughout pregnancy without a change in dose. (See "Wilson disease: Management", section on 'Pregnancy and lactation'.)

At-risk relatives — First-degree relatives of an individual with Wilson disease are at risk for inheriting the variant. This includes relatives of a tested individual who is homozygous for a pathogenic variant and relatives of a tested individual who is compound heterozygous for two different pathogenic variants. If the pathogenic variants in an affected family member are known, molecular testing for previously identified familial variants allows for early diagnosis and initiation of therapy in siblings prior to the development of symptoms.

●Offspring of an individual with homozygous or compound heterozygous variants in ATP7B will typically inherit one of the variants. If the other parent also carries an ATP7B variant, it is possible for the offspring to be homozygous or compound heterozygous for pathogenic or likely pathogenic variants in ATP7B and, thus, affected with Wilson disease.

●Full siblings of an individual who has homozygous or compound heterozygous variants in ATP7B typically have a 25 percent chance of also having homozygous or compound heterozygous variants in ATP7B and a 50 percent chance of being a carrier (heterozygote) with a single ATP7B variant if they have the same biological parents.

If indicated, testing should generally be deferred in asymptomatic individuals until the tested individual's results have been reviewed and caveats are addressed. In those less than 18 years of age, testing should be performed in concert with parents or guardians to allow for proper informed consent. (See 'How to read the report' above and "Genetic testing", section on 'Ethical, legal, and psychosocial issues' and "Gene test interpretation: ATM (ataxia-telangiectasia, breast cancer, and pancreatic cancer susceptibility gene)", section on 'How to read the report'.)

Discussions of risk and initial testing can be performed by the relative's primary clinician. If the relative requires counseling, additional information, or testing that cannot be provided by the primary clinician, referral for genetic counseling is recommended. (See 'Resources' below and "Gene test interpretation: ATM (ataxia-telangiectasia, breast cancer, and pancreatic cancer susceptibility gene)", section on 'Resources'.)

IMPLICATIONS OF VARIANTS OF UNCERTAIN SIGNIFICANCE — Individuals with a variant of uncertain significance (VUS) should be managed based on their personal and family history (algorithm 1). Patients with both a VUS and a single pathogenic variant and those with biallelic VUSs require careful phenotypic characterization for manifestations of Wilson disease. For a VUS, new information may become available, and the testing laboratory or other resource should be consulted periodically for updates in classification (eg, annually). (See "Wilson disease: Clinical manifestations, diagnosis, and natural history", section on 'Diagnostic evaluation'.)

IMPLICATIONS OF A NEGATIVE TEST — Negative testing means no pathogenic or likely pathogenic variants were identified. However, some tests only query a subset of variants; pathogenic variants might still be present (algorithm 1).

●If the familial variant(s) in ATP7B are known and the tested individual tests negative, usually they can be reassured that they are not at risk for Wilson disease.

●If a familial variant in ATP7B is not known and results of genetic testing are negative, additional testing for other variants in other parts of the gene (if testing was not comprehensive) may be needed. Management is based on clinical symptoms and biochemical testing. Referral for genetic counseling may be helpful to determine optimal testing.

RESOURCES

UpToDate topics

●Epidemiology and pathogenesis of Wilson disease – (See "Wilson disease: Epidemiology and pathogenesis".)

●Clinical manifestations and diagnosis of Wilson disease – (See "Wilson disease: Clinical manifestations, diagnosis, and natural history".)

●Management of Wilson disease – (See "Wilson disease: Management".)

Locating a genetics expert

●Genetic counselor – The National Society of Genetic Counselors (NSGC)

●Clinical geneticist – The American College of Medical Genetics and Genomics (ACMG)