Peroxisome Biogenesis Disorders, Zellweger Syndrome Spectrum via the PEX1 Gene

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
3087 PEX1 81479 81479,81479 $640 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
3087PEX181479 81479 $640 Order Options and Pricing

Pricing Comments

This test is also offered via our exome backbone with CNV detection (click here). The exome-based test may be higher priced, but permits reflex to the entire exome or to any other set of clinically relevant genes.

A 25% additional charge will be applied to STAT orders. View STAT turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

Turnaround Time

18 days on average

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

Peroxisome Biogenesis Disorders, Zellweger Syndrome Spectrum (PBD-ZSS) consist of three related diseases (Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), and Infantile Refsum disease (IRD)) that share overlapping phenotypes with severity ranging from ZS to IRD. The overall incidence of PBD-ZSS is estimated to be from 1:500,000 to 1:50,000 (Steinberg et al. 2012). Common clinical features to all three include neurodevelopmental delay, glaucoma, retinal dystrophy, impaired hearing, renal cysts, and hepatic dysfunction (Wanders and Waterham 2005). Zellweger syndrome (ZS) is the most severe, neonatal onset, and characterized by typical craniofacial dysmorphism and profound hypotonia, severe seizures, and inability to feed. Infants with ZS usually do not make any developmental progress and rarely survive the first year of life. Compared to ZS, patients with NALD have less severe hypotonia and seizures during infancy and may reach school age. IRD is the least severe form. Patients with IRD show variable developmental delay and often present predominantly vision problems, sensorineural hearing loss, and liver dysfunction. Most affected patients can reach childhood and, in rare cases, survive into adulthood. It has been suggested that a peroxisome biogenesis disorder should be considered in any individuals manifesting both vision and hearing problems. Biochemical findings of a PBD-ZSS patient include elevated plasma VLCFAs (C24:0 and C26:0), phytanic acid, and pipecolate and deficient plasmalogen synthesis in erythrocytes or cultured fibroblasts. A disparity of biochemical results obtained from different specimens (plasma, cultured cells or tissues) has been reported in milder patients due to peroxisomal mosaicism. Treatments of PBD-ZSS focus on symptomatic therapy (Steinberg et al. 2012; Steinberg et al. 2006).

Genetics

PBD-ZSS are all autosomal recessively inherited and caused by pathogenic variants in one of PEX genes required for normal peroxisome assembly and/or peroxisomal protein import. The clinical severity is generally correlated with the impact of a given mutation on peroxisome formation and function (Ebberink et al, 2011). At least 13 PEX genes have been reported to be associated with PBD-ZSS (Smith and Aitchison 2013). Mutations in the PEX1 gene are the most common cause and account for nearly 70% of patients with ZS, NALD, and IRD. The mutation spectrum includes missense, nonsense, splicing site mutations, small deletion/insertions, and large deletions. The p.Ile700Tyrfs*42 (in exon 13) and p.Gly843Asp (in exon 15) variants are two common mutations found in patients with European ancestry, comprising up to 80% of alleles in individuals with mutations in PEX1 gene (Steinberg et al. 2004; Waterham and Ebberink 2012).

Clinical Sensitivity - Sequencing with CNV PG-Select

PEX1 mutations are the most common cause of PBD-ZSS and account for about 70% of affected patients. Approximately 50% of PBD-ZSS patients with European ancestry have at least one of two common mutations (p.Ile700Tyrfs*42 and p.Gly843Asp) in PEX1 exons 13 and 15 (Steinberg et al. 2004; Waterham and Ebberink 2012).

Clinical sensitivity for del/dup testing is expected to be low. Three PEX1 gross deletions affecting single- or multi- exons have been reported so far (Tamura et al. 2001).

Testing Strategy

This test provides full coverage of all coding exons of the PEX1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

Indications for Test

Individuals with clinical symptoms and biochemical findings consistent with PBD-ZSS. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in PEX1.

Gene

Official Gene Symbol OMIM ID
PEX1 602136
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Test

Name
Fetal Concerns Panel

Citations

  • Ebberink MS, Mooijer PAW, Gootjes J, Koster J, Wanders RJA, Waterham HR. 2011. Genetic classification and mutational spectrum of more than 600 patients with a Zellweger syndrome spectrum disorder. Hum. Mutat. 32: 59–69. PubMed ID: 21031596
  • Smith JJ, Aitchison JD. 2013. Peroxisomes take shape. Nat. Rev. Mol. Cell Biol. 14: 803–817. PubMed ID: 24263361
  • Steinberg et al. 2017. PubMed ID: 20301621
  • Steinberg S, Chen L, Wei L, Moser A, Moser H, Cutting G, Braverman N. 2004. The PEX Gene Screen: molecular diagnosis of peroxisome biogenesis disorders in the Zellweger syndrome spectrum. Mol. Genet. Metab. 83: 252–263. PubMed ID: 15542397
  • Steinberg SJ, Dodt G, Raymond GV, Braverman NE, Moser AB, Moser HW. 2006. Peroxisome biogenesis disorders. Biochim. Biophys. Acta 1763: 1733–1748. PubMed ID: 17055079
  • Tamura S, Matsumoto N, Imamura A, Shimozawa N, Suzuki Y, Kondo N, Fujiki Y. 2001. Phenotype-genotype relationships in peroxisome biogenesis disorders of PEX1-defective complementation group 1 are defined by Pex1p-Pex6p interaction. Biochem. J. 357: 417–426. PubMed ID: 11439091
  • Wanders RJA, Waterham HR. 2005. Peroxisomal disorders I: biochemistry and genetics of peroxisome biogenesis disorders. Clin. Genet. 67: 107–133. PubMed ID: 15679822
  • Waterham HR, Ebberink MS. 2012. Genetics and molecular basis of human peroxisome biogenesis disorders. Biochim. Biophys. Acta 1822: 1430–1441. PubMed ID: 22871920

Ordering/Specimens

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Specimen Types

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