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  • Test code: 06211
  • 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
  • Sample requirements
  • Request a sample kit
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Invitae Zellweger Spectrum Disorder Panel

Test description

The Invitae Zellweger Spectrum Disorder panel analyzes 15 genes associated with peroxisomal biogenesis disorders that can cause Zellweger Spectrum Disorder (ZSD). This panel may be appropriate for individuals with signs and symptoms of a peroxisomal biogenesis disorder. Additionally, this panel may be appropriate for those in whom a ZSD is suspected due to abnormal plasma very-long-chain fatty acids (VLCFA) or phytanic acid and pristanic acid levels. Genetic testing of these genes may confirm a diagnosis and help guide treatment and management decisions.

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Primary panel (15 genes)

ACOX1 AMACR HSD17B4 PEX1 PEX10 PEX12 PEX13 PEX14 PEX16 PEX19 PEX2 PEX26 PEX3 PEX5 PEX6

  • Zellweger syndrome
  • neonatal adrenoleukodystrophy (NALD)
  • infantile Refsum disease (IRD)
  • peroxisomal acyl-CoA oxidase deficiency
  • D-bifunctional protein (DBP) deficiency
  • alpha-methylacyl-CoA racemase deficiency (AMACRD)
  • congenital bile acid synthesis defect 4 (CBAS4)

Zellweger spectrum disorder (ZSD), a peroxisomal biogenesis disorder (PBD), is comprised of three clinical subtypes: Zellweger syndrome, neonatal adrenoleukodystrophy (NALD), and infantile Refsum disease (IRD). Zellweger syndrome is on the most severe end of the spectrum, NALD is intermediate, and IRD is the least severe subtype.

  • Zellweger syndrome presents in infancy with hypotonia, feeding difficulties, seizures, liver dysfunction, dysmorphic facial features, retinal dystrophy, sensorineural hearing loss, and chondrodysplasia punctata. Infants with Zellweger syndrome typically do not survive beyond the first year of life.
  • NALD and IRD typically present in late infancy or early childhood with developmental delay, vision problems, hearing loss, intellectual disability, liver dysfunction and hypotonia. Some present with spontaneous episodes of hemorrhage, such as intracranial bleeding. Developmental milestones may be lost as the disease progresses. Most individuals with NALD survive into childhood, and those with IRD may survive into adulthood.

Defects in the oxidation of very-long-chain fatty acid (VLCFA) and pristanic acid can present with overlapping phenotypic and biochemical features of ZSS. Single peroxisomal enzyme deficiencies included on this panel are peroxisomal acyl-CoA oxidase deficiency, D-bifunctional protein (DBP) deficiency, and alpha-methylacyl-CoA racemase deficiency (AMACRD).

This test is estimated to identify pathogenic variants in at least 85% of patients with ZSD.

Gene* % ZSD attributed to pathogenic variants by each gene
PEX1 58-68%
PEX6 10.7-16%
PEX26 3-6.6%
PEX10 3-4.6%
PEX12 4.1-9%
PEX2 1-4%
PEX3 ~1-1.5%
PEX5 1.5-2%
PEX13 ~1%
PEX14 ~0.5%
PEX16 0.5-1%
PEX19 ~0.5%

*ACOX1, AMACR, and HSD17B4 cause the single peroxisomal enzyme deficiencies, peroxisomal acyl-CoA oxidase (ACOX1) deficiency, 2-methylacyl-CoA racemase deficiency, and D-bifunctional protein deficiency, respectively. These disorders can look like Zellweger spectrum clinically or biochemically.

Zellweger spectrum disorder is inherited in an autosomal recessive manner.

Zellweger spectrum disorder is estimated to occur in 1 in 50,000 individuals.

This test may be appropriate for patients with:

  • features consistent with Zellweger syndrome, neonatal adrenoleukodystrophy, or infantile refsum disease
  • patients with elevated VLCFAs, phytanic acid, pristanic acid, pipecolic acid, and low plasmalogens

For more information, please refer to:

  1. Braverman, NE, et al. Peroxisome biogenesis disorders in the Zellweger spectrum: An overview of current diagnosis, clinical manifestations, and treatment guidelines. Mol. Genet. Metab. 2016; 117(3):313-21. PMID: 26750748
  2. Braverman, NE, et al. Peroxisome biogenesis disorders: Biological, clinical and pathophysiological perspectives. Dev Disabil Res Rev. 2013; 17(3):187-96. PMID: 23798008
  3. Wanders, RJ. Metabolic and molecular basis of peroxisomal disorders: a review. Am. J. Med. Genet. A. 2004; 126A(4):355-75. PMID: 15098234
  4. Aubourg, P, Wanders, R. Peroxisomal disorders. Handb Clin Neurol. 2013; 113:1593-609. PMID: 23622381
  5. Suzuki, Y, et al. Peroxisomal acyl CoA oxidase deficiency. J. Pediatr. 2002; 140(1):128-30. PMID: 11815777
  6. Carrozzo, R, et al. Peroxisomal acyl-CoA-oxidase deficiency: two new cases. Am. J. Med. Genet. A. 2008; 146A(13):1676-81. PMID: 18536048
  7. Ferdinandusse, S, et al. Mutational spectrum of D-bifunctional protein deficiency and structure-based genotype-phenotype analysis. Am. J. Hum. Genet. 2006; 78(1):112-24. PMID: 16385454
  8. Lines, MA, et al. Peroxisomal D-bifunctional protein deficiency: three adults diagnosed by whole-exome sequencing. Neurology. 2014; 82(11):963-8. PMID: 24553428
  9. Setchell, KD, et al. Liver disease caused by failure to racemize trihydroxycholestanoic acid: gene mutation and effect of bile acid therapy. Gastroenterology. 2003; 124(1):217-32. PMID: 12512044
  10. Smith, EH, et al. An adult onset case of alpha-methyl-acyl-CoA racemase deficiency. J. Inherit. Metab. Dis. 2010; 33 Suppl 3:S349-53. PMID: 20821052
  11. Steinberg, SJ, et al. Peroxisome Biogenesis Disorders, Zellweger Syndrome Spectrum. 2003 Dec 12. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301621
  12. Tien Poll-The B, Aubourg P, Wanders RJA. Inborn metabolic diseases: diagnosis and treatment. 5th ed. Heidelberg: Springer; 2012. Chapter 41, Peroxisomal Disorders; p. 591-605.

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
ACOX1 NM_004035.6
AMACR NM_014324.5
HSD17B4 NM_000414.3
PEX1 NM_000466.2
PEX10 NM_153818.1
PEX12 NM_000286.2
PEX13 NM_002618.3
PEX14 NM_004565.2
PEX16 NM_004813.2
PEX19 NM_002857.3
PEX2 NM_000318.2
PEX26 NM_017929.5
PEX3 NM_003630.2
PEX5 NM_001131025.1
PEX6 NM_000287.3