Wilson disease is a rare inherited disorder of copper metabolismin which excess copper is deposited throughout the tissues, especially in the liver, brain, and eyes. Approximately 1 in every 30,000 people are affected, who exhibit a wide range of symptoms, including liver disease, neurological impairments, and psychiatric disorders.1


Wilson disease is inherited in an autosomal-recessive pattern, in which both parents must carry an abnormal copy of the ATP7B gene to pass the disorder on to their children. At conception, each child has a 25% probability of being affected by Wilson disease, a 25% probability of being completely unaffected, and a 50% chance of becoming an asymptomatic carrier (like the parents).2 

Once pathogenic ATP7B gene variants have been confirmed in a family, it is important for all at-risk first-degree relatives (siblings) to undergo molecular genetic testing to determine if they have Wilson disease or are carriers of an abnormal genetic variant. Carriers along with their partners may benefit from genetic counseling before starting a family, so that they understand the probability that 2 people with their combination of genetics will pass Wilson disease on to their children. Pregnant women whose children are at risk for Wilson disease may choose to undergo prenatal testing or preimplantation genetic testing to confirm whether a fetus has the disease.2

ATP7B Variants

According to the literature, more than 600 pathogenic variants of the ATP7B gene had been identified by 2017. More than 50% of ATP7B variants involve single-nucleotide missense and nonsense mutations, which are followed in frequency by insertions or deletions. Splice site mutations rarely occur.3,4

The most common ATP7B variant in people of central or eastern European descent is the missense mutation His1069Gln, located on exon 14. Throughout the eastern European countries, the frequency of the His1069Gln mutation ranges from 57% to 72% according to geographical location. The His1069Gln missense mutation is also the most common variant in North America, with an allele frequency of approximately 40%.4

Carriers are more numerous in certain ethnic groups as a consequence of consanguinity, which leads to relatively high prevalence of disease, with different mutational patterns observed in specific regions. For example, the prevalence of the deletion c.-441_-427del15 in the ATP7B gene promoter region is 60% in Sardinia, whereas the prevalence of the ATP7B variant p.Leu708Pro is 64% in the Canary Islands. Another region where the prevalence of ATP7B gene mutations is relatively high is Costa Rica; the prevalence of the N1270S mutation is 61%.4 

The prevalence of ATP7B variants is lower in Japan, China, and Korea than in Costa Rica, Sardinia, and the Canary Islands. The most common ATP7B variant in these countries is the missense mutation R778L, which is located on exon 8; the allele frequency ranges from 12% to 45%. Two ATP7B deletions, 2871delC and 2874delC, are also commonly reported throughout Japan.4   

Pathogenesis of Wilson Disease

The ATP7B gene, located on chromosome 13q14.3, contains 20 introns and 21 exons. It forms within the endoplasmic reticulum and is transported to the trans-Golgi network within the liver.3

Variants of the ATP7B gene encode dysfunctional ATP7B copper transporter proteins, the result of impaired protein folding. Improper folding affects protein function; the transport of excess copper from the liver into the biliary system is prevented, as is the loading of 6 copper ions onto apoceruloplasmin to convert it to active ceruloplasmin. The plasma protein ceruloplasmin transports copper from the liver to the rest of the body through the blood, which is why excess copper is deposited throughout tissues and organs other than the liver.3,5,6 

Research has shown that the predominant missense mutation, H1069Q, causes protein misfolding, which alters the orientation and affinity of the ATP binding site. As a result, phosphorylation of the P-domain of the ATP7B copper transport protein, which requires ATP as a source of energy to transport copper across cellular membranes, is impaired.3,4

Genotype-Phenotype Correlation

Several sources indicate that genotype correlates poorly with phenotypic manifestations of Wilson disease.3,4 In one study, patients in eastern Sicily who all had an identical ATP7B variant genotype demonstrated a wide range of disease manifestations. The mutation c.3904-2A > G can be associated in the Mediterranean population with this phenotypic variability. Further investigations with whole exome analysis or next generation sequencing are suggested.7 

Other studies suggest that genotype correlates with the degree of functional impairment of the ATP7B copper transport protein, reducing the stability of the protein to varying degrees according to the ability of ATP to bind to the protein. Some mutations only partially impair this ability, allowing some ATP binding and copper transport activity. ATP7B variants also result in mislocalization of the ATP7B proteins to incorrect cell compartments.4,8,9 Following an analysis of 28 different ATP7B variants obtained from patients with Wilson disease, researchers concluded that single assays cannot accurately predict phenotypic expression of the disease on the basis of a specific ATP7B variant.9

Genetic Modifiers of Wilson Disease

Studies have shown that normal variations of the PRNP gene may modify the course of Wilson disease. The PRNP gene codes for a prion protein that assists with copper transport within the brain and other tissues. In patients with Wilson disease who have the amino acid methionine at position 129 on the prion protein instead of valine, the onset of predominantly neurological symptoms is delayed.1

Other possible genetic modifiers affecting disease phenotype include MTHFR, COMMD1, ATOX1, XIAP, PNPLA3, and DMT1. However, none of these genes have demonstrated significant predictive or diagnostic value. Significant phenotypic variation of Wilson disease exists between individuals within the same family, monozygotic twins, and individuals with the same mutation.3


  1. Wilson disease. MedlinePlus. Accessed September 20, 2022. 
  2. Weiss KH. Wilson disease.  GeneReviews [Internet]. Updated July 29, 2016. Accessed September 20, 2022. 
  3. Chang IJ, Hahn SH. The genetics of Wilson disease. Handb Clin Neurol. 2017;142:19-34. doi:10.1016/B978-0-444-63625-6.00003-3
  4. Medici V, LaSalle JM. Genetics and epigenetic factors of Wilson disease. Ann Transl Med. 2019;7(Suppl 2):S58-S58. doi:10.21037/atm.2019.01.67
  5. Gilroy RK. Wilson disease: etiology. Medscape. Updated February 14, 2019. Accessed September 20, 2022.
  6. Linder MC. Apoceruloplasmin: abundance, detection, formation, and metabolism. Biomedicines. 2021;9(3):233. doi:10.3390/biomedicines9030233
  7. Sapuppo A, Pavone P, Praticò AD, Ruggieri M, Bertino G, Fiumara A. Genotype-phenotype variable correlation in Wilson disease: clinical history of two sisters with the similar genotype. BMC Med Genet. 2020;21:128. doi:10.1186/s12881-020-01062-6
  8. Huster D, Hoppert M, Lutsenko S, et al. Defective cellular localization of mutant ATP7B in Wilson’s disease patients and hepatoma cell lines. Gastroenterology. 2003;124(2):335-345. doi:10.1053/gast.2003.50066 
  9. Huster D, Kühne A, Bhattacharjee A, et al. Diverse functional properties of Wilson disease ATP7B variants. Gastroenterology. 2012;142(4):947-956.e5. doi:10.1053/j.gastro.2011.12.048

Reviewed by Debjyoti Talukdar, MD, on 9/29/2022.