Welcome to the Gene Scene! Each week, we will explore a gene from the ACMG Secondary Findings list—genes identified by the American College of Medical Genetics and Genomics as having clear, actionable health implications. These genes are included because they’re linked to serious but preventable or manageable conditions when identified early. Here, we focus on the condition that led to the gene’s inclusion on the list, providing clear, relevant information that supports your clinic. To subscribe to the Gene Scene, contact your local GSL or send a request to info@ambrygen.com. 

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Clinical Phenotype Summary: 

The ATP7B gene is located on chromosome 13q14.3 with 21 exons and encodes the copper-transporting ATPase 2 protein, which acts as a plasma membrane copper transport protein. Pathogenic variants in this gene are known to cause Wilson disease, which is inherited in an autosomal recessive fashion.

Wilson disease is characterized by a build-up of intracellular hepatic copper in liver and brain and can present with the following:

• Kayser-Fleischer rings
• Hepatic symptoms
  • Recurrent jaundice 
  • Hepatitis
  • Hepatic failure
  • Chronic liver disease
• Neurological abnormalities 
  • Movement disorders including tremor, poor coordination, and loss of fine motor control
  • Psychiatric disturbance including depression, neurotic behaviors, disorganization of personality

Variability in age of onset as well as clinical features between and within families have been reported. Age of onset has been reported between 8 months of age and >50 years of age. Biallelic loss of function has been reported as the mechanism of disease for Wilson disease.

Unique Considerations: 

Patients with one or two truncating alterations have been shown to have lower serum copper and ceruloplasmin levels with an earlier age of onset compared to patients with two missense alterations, and the effect of truncating alterations appears to be dosage-dependent. Findings from 69 families with Wilson disease and suggested that the p.H1069Q and p.R969Q missense alterations specifically appeared to result in a more mild phenotype with a later onset of symptoms.  

Clinical Resources: 

Understanding Your Positive Exome Sequencing Test Result

Understanding Your Uncertain Exome Sequencing Test Result 

Understanding Your Negative Exome Sequencing Test Result

Understanding Your Positive Secondary Findings Test Result 

Citations: 

Abuduxikuer K, et al. (2015) World J Gastroenterol 21(29):8981-8984. PMID: 26269689

De Bie P, et al. (2007) J Med Genet 44:673-688. PMID: 17717039

Gromadzka G, et al. (2005) Clin Genet 68:524-532. PMID: 16283883

Ivanova II, et al. (2015) Clin J Gastroenterol 8(1):52-6. 

Panagiotakaki E, et al. (2004) Am J Med Genet 131A:168-173. PMID: 15523622

Ambry Genetics Gene-Disease Validity Scheme

Each week, we explore a gene from the ACMG Secondary Findings list—genes identified by the American College of Medical Genetics and Genomics as having clear, actionable health implications. These genes are included because they’re linked to serious but preventable or manageable conditions when identified early. 

To learn more about the ACMG Secondary Findings list, click here.

To read all previous Gene Scene emails, click here.