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  • Test code: 06202
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
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Invitae Copper Metabolism Disorders Panel

Test description

The Invitae Copper Metabolism Disorders panel analyzes 5 genes associated with copper transport diseases. This panel may be appropriate for individuals with signs and symptoms of a copper transport disease. Genetic testing of these genes may confirm a diagnosis, help guide treatment and management decisions and provide adequate genetic counseling. Identification of disease-causing variants provide accurate risk assessment and determine carrier status in at-risk relatives.

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Primary panel (5 genes)
  • aceruloplasminemia
  • ATP7A-related distal motor neuropathy
  • Huppke-Brendel syndrome
  • MEDNIK syndrome (mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma)
  • Menkes disease
  • occipital horn disease
  • Wilson disease

Copper transport disorders (CTDs) comprise a disparate group of conditions involving disruption of copper homeostasis. Copper is an essential metal and is involved in numerous cellular processes including mitochondrial respiration, neurotransmitter synthesis, connective tissue formation, skin pigmentation and antioxidant defense. The majority of copper in humans is associated with enzymes or bound to proteins, and 95% of copper is incorporated into ceruloplasmin. Maintaining adequate copper concentrations is essential as both excessive copper storage and lack of copper can lead to potentially fatal diseases.

Aceruloplasminemia is not a disorder of copper metabolism, but the absence of the copper-containing enzyme, ceruloplasmin (95% of copper in humans is contained in ceruloplasmin). Ceruloplasmin plays a critical role in the efflux of iron from cells. Aceruloplasminemia gradually leads to excessive iron accumulation in the eye, brain and pancreas causing the classic features of neurologic disease, retinal degeneration and diabetes mellitus. Neurologic features of aceruloplasminemia including chorea, cerebellar ataxia, dystonia, parkinsonism and psychiatric illness, present in adulthood and progress without treatment with iron chelating agents. Biochemical findings include low serum copper and ceruloplasmin levels, low serum iron, high serum ferritin and increased hepatic iron concentrations.

ATP7A-related conditions occur due to generalized copper deficiency and include Menkes disease, Occipital horn disease, ATP7A-related distal motor neuropathy. There is a broad phenotypic spectrum ranging from early infantile onset, fatal disease to adult onset neuropathy. Menkes is the most severe presentation and affected males present with neurologic symptoms such as hypotonia and seizures, and progressive neurologic decline. Hair, skin and vascular abnormalities are also observed and death typically occurs by 3-4 years of age. Occipital horn syndrome is a milder form presenting in early to middle childhood with connective tissue abnormalities. The central nervous system may also be affected and most individuals live until mid-adulthood. ATP7A-related distal motor neuropathy is an adult-onset neuropathy resembling Charcot-Marie-Tooth.

Huppke-Brendel syndrome is a very rare disorder of copper metabolism due to defects in acetylation of one or more copper proteins. It is characterized by congenital cataracts, sensorineural deafness, severe developmental delay and low serum copper and ceruloplasmin levels. All reported patients have died in early childhood.

MEDNIK (Mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma) is a rare multisystemic condition due to abnormal intracellular trafficking of the copper pumps ATPTA and ATP7B. This leads to secondary deficiency of copper-dependent enzymes. It combines clinical and biochemical features of both Menkes and Wilson diseases. The neurologic, cutaneous and skeletal findings, along with low plasma copper and ceruloplasmin can be similar to Menkes disease, although milder. Liver disease with excessive copper accumulation, abnormal brain MRI findings and increased urinary copper excretion are similar to features of Wilson disease.

Wilson disease is a disorder of excessive copper accumulation. Individuals with Wilson disease often present with liver disease (40%), neurologic disease (40%), and psychiatric disturbance (20%); most have Kayser Fleischer rings on ophthalmologic exam. Other findings include renal involvement, arthritis, osteoporosis, pancreatitis, cardiomyopathy, and sunflower cataracts. Hepatocellular carcinoma rarely develops. Biochemical findings include increased urinary copper excretion and low serum copper and ceruloplasmin levels. Medical management with chelating agents and zinc are useful to reduce symptoms. Liver transplantation has been utilized for those not responsive to medical management.

  • For patients with clinical symptoms of Wilson disease, sequence variants in the gene ATP7B are identified in more than 98% of patients. Deletions/duplications in this gene are rare.
  • 95%–100% of cases with a clinical diagnosis of Menkes disease will possess a pathogenic variant in the protein-coding regions of ATP7A.
  • Greater than 92% of individuals with a clinical diagnosis of aceruplasminemia will have pathogenic variants in CP.

All of the copper transport disorders follow autosomal recessive inheritance, except the APT7A-related conditions (Menkes disease, occipital horn disease, ATP7A-related distal motor neuropathy) These conditions are X-linked.

ATP7A-related conditions have an estimated incidence of 1: 300,000 although ATP7A-related distal motor neuropathy may be underdiagnosed.

Aceruloplasminemia has an estimated prevalence of 1:2,000,000 individuals in Japan.

MEDNIK and Huppke-Brendel syndromes are very rare conditions with an unknown incidence.

ATP7A biochemical testing is unreliable in females and cannot be used to determine carrier status. Molecular studies are the only reliable way to determine carrier status.

  1. Miyajima, H. Aceruloplasminemia. 2003 Aug 12. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301666
  2. Gaetke, LM, et al. Copper: toxicological relevance and mechanisms. Arch. Toxicol. 2014; 88(11):1929-38. PMID: 25199685
  3. Martinelli, D, et al. MEDNIK syndrome: a novel defect of copper metabolism treatable by zinc acetate therapy. Brain. 2013; 136(Pt 3):872-81. PMID: 23423674
  4. Chiplunkar, S, et al. Huppke-Brendel syndrome in a seven months old boy with a novel 2-bp deletion in SLC33A1. Metab Brain Dis. 2016; 31(5):1195-8. PMID: 27306358
  5. Martinelli, D, Dionisi-Vici, C. AP1S1 defect causing MEDNIK syndrome: a new adaptinopathy associated with defective copper metabolism. Ann. N. Y. Acad. Sci. 2014; 1314:55-63. PMID: 24754424
  6. Huppke, P, et al. Mutations in SLC33A1 cause a lethal autosomal-recessive disorder with congenital cataracts, hearing loss, and low serum copper and ceruloplasmin. Am. J. Hum. Genet. 2012; 90(1):61-8. doi: 10.1016/j.ajhg.2011.11.030. PMID: 22243965
  7. Gialluisi, A, et al. The homozygosity index (HI) approach reveals high allele frequency for Wilson disease in the Sardinian population. Eur. J. Hum. Genet. 2013; 21(11):1308-11. PMID: 23486543
  8. Coffey, AJ, et al. A genetic study of Wilson's disease in the United Kingdom. Brain. 2013; 136(Pt 5):1476-87. PMID: 23518715
  9. Chen, C, et al. Currently Clinical Views on Genetics of Wilson's Disease. Chin. Med. J. 2015; 128(13):1826-30. PMID: 26112727
  10. van, Meer, S, et al. No increased risk of hepatocellular carcinoma in cirrhosis due to Wilson disease during long-term follow-up. J. Gastroenterol. Hepatol. 2015; 30(3):535-9. PMID: 25160780
  11. Bruha, R, et al. Long-term follow-up of Wilson disease: natural history, treatment, mutations analysis and phenotypic correlation. Liver Int. 2011; 31(1):83-91. PMID: 20958917
  12. Roberts, EA, et al. Diagnosis and treatment of Wilson disease: an update. Hepatology. 2008; 47(6):2089-111. PMID: 18506894
  13. Kaler, SG. ATP7A-Related Copper Transport Disorders. 2003 May 09. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301586
  14. Tümer, Z, Møller, LB. Menkes disease. Eur. J. Hum. Genet. 2010; 18(5):511-8. PMID: 19888294
  15. Tümer, Z, Klomp, L. Clinical utility gene card for: Menkes disease. Eur. J. Hum. Genet. 2011; 19(10):None. PMID: 21487442
  16. Smpokou, P, et al. Menkes disease in affected females: the clinical disease spectrum. Am. J. Med. Genet. A. 2015; 167A(2):417-20. PMID: 25428120
  17. Woimant, F, Trocello, JM. Disorders of heavy metals. Handb Clin Neurol. 2014; 120:851-64. PMID: 24365357

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
AP1S1 NM_001283.3
ATP7A NM_000052.6
ATP7B NM_000053.3
CP NM_000096.3
SLC33A1 NM_004733.3