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Zellweger Spectrum Disorders NGS Panel


Syndrome Information

Clinical Description

Zellweger spectrum disorders (ZSD) consist of Zellweger syndrome (cerebro-hepato-renal syndrome; most severe phenotype), neonatal adrenoleukodystrophy (NALD; intermediate phenotype) and infantile Refsum disease (IRD; mildest phenotype).  ZSD are associated with abnormal brain development, liver dysfunction, skeletal and renal defects.  Zellweger syndrome patients are severely affected from birth; they are dysmorphic, hypotonic, developmentally delayed and have failure to thrive.  In contrast, IRD patients have visual and auditory sensory deficits, with or without developmental delay, as their main features.  ZSD patients have elevated plasma very long chain fatty, deficient red blood cell plasmalogens, and elevated plasma and/or urine pipecolic acid.  Some patients have equivocal blood metabolite levels and may need further metabolic testing in cultured fibroblasts or DNA testing to make a final diagnosis.  Copies of the patient's biochemical analysis are extremely helpful in result interpretation.

Inheritance Pattern

Autosomal Recessive; Autosomal Dominant

Genotype-Phenotype Correlation

Missense mutations may be associated with milder clinical and biochemical phenotypes; however, this can be specific to certain mutations in certain genes. 

Test Information

Test Method

Next Generation Sequencing (NGS) of the coding regions and intron-exon boundaries of the listed genesDeletion/Duplication:  Dosage analysis by normalization of NGS read depth for the listed genes (except DNM1L); Sanger sequencing for potential fill in / confirmation 

This test is also available as part of one or more NGS panels for peroxisomal disorders.

Clinical Utility

Identification of causative mutations in known or highly suspicious cases of ZSD based on clinical presentation and the blood biomarker profile; rule-out ZSD in the presence of equivocal clinical presentation and/or biomarker profile; targeted carrier testing of relatives of proband; predictive prenatal testing when familial mutations are known. 

Clinical Sensitivity

Sequencing:  The sequencing panel will detect at least one mutation in 99% of patients.  Two causative mutations in a single gene should be identified in at least 98% of patients.  There have been individual case reports of deletions/duplications in multiple PEX genes, but no published case series. 

Analytic Sensitivity

> 99% for inherited single nucleotide and small insertion/deletion variants for the nucleotides evaluated; >99% for multi-exon deletions and >98% for single exon deletions; >90% for multi-exon duplications and >75% for single exon duplications. Lower limit of detection for single nucleotide variants: 25% allele frequency (>99% sensitivity).

Sample Requirements

3-6ml whole blood in EDTA (purple topped) tubes. (see Pediatric or Adult blood sample algorithms for additional information)

We prefer whole blood for all tests.

Turn Around Time

Approximately 4 weeks

Fee and CPT Codes

NGS Panel:  $3211 for routine testing
CPT Code:  81479 x 13

Special Considerations

We request that copies of the patient's biochemical analysis be submitted with the sample.

Digenic inheritance (disease caused by mutations in 2 different PEX genes) has not been reported, but remains a theoretical possibility.  

NGS panels for peroxisomal disorders.

INFORMED CONSENT from the patient is required prior to ordering a genetic test. The DNA Diagnostic Lab's consent is located on the second page of the requisition form. There is also a patient brochure, "Things Every Patient Should Know Before Consenting to a Genetic Test", available for download.