Peroxisomal Disorders Panel

Peroxisomal disorders are genetically heterogeneous metabolic diseases, and are divided into peroxisomal biogenesis disorders and peroxisomal single protein defects.

Peroxisomal biogenesis disorders (PBDs) are caused by defects in peroxisome assembly and formation. Clinical features and biochemical findings are associated with multiple abnormal enzymatic pathways in peroxisomes. PBDs include Peroxisome Biogenesis Disorders, Zellweger Syndrome Spectrum (PBD-ZSS) and PEX7-related disorders (rhizomelic chondrodysplasia punctata Type 1 and adult Refsum disease). PBD-ZSS consists of three related diseases (Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), and Infantile Refsum’s disease (IRD)) that share overlapping phenotypes with severity ranging from ZS to IRD (Steinberg et al. 2017. PubMed ID: 20301621).

Peroxisomal single protein defects include X-linked adrenoleukodystrophy (X-ALD), PHYH-related adult Refsum disease, rhizomelic chondrodysplasia punctata type 2 and type 3, congenital bile acid synthesis defect-4 and -5, D-bifunctional enzyme deficiency, acyl-CoA oxidase deficiency (also called pseudoneonatal adrenoleukodystrophy), primary hyperoxaluria type 1, acatalasemia, leukoencephalopathy with dystonia and motor neuropathy, and Mulibrey nanism. X-ALD is the most common inherited peroxisomal disorder and affects 1 in 18,000 individuals (Wanders and Waterham. 2006. PubMed ID: 17055078).

This NextGen test analyzes multiple genes involved in both peroxisomal biogenesis disorders and peroxisomal single protein defects. Except in the case of the ABCD1 and DNM1L genes, peroxisomal disorders are inherited in an autosomal recessive manner and caused by loss-of function variants in the relevant gene. X-linked adrenoleukodystrophy (ABCD1 gene) is inherited in an X-linked recessive manner. DNM1L-assocated diseases can be autosomal dominant secondary to dominant-negative missense variants (Waterham et al. 2007. PubMed ID: 17460227) or be a recessive disorder due to loss-of-function variants (Yoon et al. 2014. PubMed ID: 26825290).

Peroxisome Biogenesis Disorders, Zellweger Syndrome Spectrum (PBD-ZSS): PEX1, PEX2, PEX3, PEX5, PEX6, PEX10, PEX11B, PEX12, PEX13, PEX14, PEX16, PEX19, PEX26, DNM1L

X-linked adrenoleukodystrophy (X-ALD): ABCD1

Rhizomelic chondrodysplasia punctate (RCDP): PEX7, GNPAT, AGPS

Adult Refsum disease (ARD): PHYH, PEX7

Congenital bile acid synthesis defect-5: ABCD3

Congenital bile acid synthesis defect-4: AMACR

D-bifunctional enzyme deficiency: HSD17B4

Acyl-CoA oxidase deficiency: ACOX1

Primary hyperoxaluria type 1: AGXT

Acatalasemia: CAT

Leukoencephalopathy with dystonia and motor neuropathy: SCP2

Mulibrey nanism: TRIM37

See individual gene test descriptions for detailed information on clinical features, molecular biology of gene products, and spectra of pathogenic variants.

Pathogenic variants in the PEX genes account for nearly all cases of clinically and biochemically diagnosed Peroxisome Biogenesis Disorders, Zellweger Syndrome Spectrum (PBD-ZSS). The overall sensitivity of this sequencing panel test is predicted to be over 95% for DNA substitutions (missense, nonsense, splicing pathogenic variants), small insertions and/or deletions (frameshift and splice-site pathogenic variants) and gross deletions and duplications. PHYH pathogenic variants account for more than 90% of patients with Adult Refsum disease. PEX7-Related Adult Refsum disease is very rare, and less than 10 patients have been reported to date (Jansen et al. 2004. PubMed ID: 14974078). Over 99% of patients with X-linked adrenoleukodystrophy have ABCD1 pathogenic variants which can be detected by sequencing with copy number variant detection of gross deletions and duplications (http://www.x-ald.nl; Raymond et al. 2018. PubMed ID: 20301491). PEX7 pathogenic variants account for over 90% of all individuals with rhizomelic chondrodysplasia punctate (RCDP). The remaining 10% are caused by defects in GNPAT and AGPS (Braverman et al. 2012. PubMed ID: 20301447). To date, only about 20 patients with RCDP type 2 and less than 10 patients with RCDP type 3 have been reported (Thai et al. 2001. PubMed ID: 11152660; Itzkovitz et al. 2012. PubMed ID: 21990100). Other disorders covered by the panel are rare and the clinical sensitivity of this panel for these disorders is unknown.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 99.9% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).

Due to known ABCD1 pseudogenes, exons 7-10 of the ABCD1 gene are analyzed via Sanger sequencing.