| DNA Diagnostic Laboratory at Johns Hopkins |  |
| DNA Diagnostic Laboratory at Johns Hopkins | |
Zellweger Spectrum Disorders |
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| Gene:
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PEX1; chr7q21.2 PEX2; chr8q21.1 PEX6; chr6p21.1 |
PEX10; chr1p36.32 PEX12; chr17q12 PEX26; chr22q11.21 |
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| 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. |
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| Inheritance Pattern: | Autosomal Recessive | |||
| 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. |
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| Test Information | ||||
| Test Method: | Bidirectional
sequencing of select coding regions or the full coding sequence of
multiple PEX genes, depending on the test panels ordered.
See Clinical Sensitivity and Fee and CPT Codes sections (below), the PEX Gene Screen Algorithm, and the Test Instructions form. |
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| 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. |
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| Clinical Sensitivity: | PEX1
panel 1 (exons 13, 15, 18, 19): 50% of patients have at least one
mutation in this panel; 25% will have both mutations
identified
PEX1 panel 2 (remaining PEX1 exons): 6-18% of patients will have both mutations identified by this panel alone; Panels one and two together will identify both mutations in at least 55% of patients PEX reflex panel (PEX2 e4; PEX6 e1; PEX10 e4, 5; PEX12 e2, 3; PEX26 e2, 3): This panel will identify both mutations in 17% of patients; an additional 5% of patients will have a single mutation identified. PEX Extra Panel (PEX10 e2, 3, 6; PEX12 e1; PEX26 e4, 5, 6): This panel will identify at least one mutationin 0-2% of patients in whom all other test panels have been negative. PEX6 panel (remaining PEX6 exons): full PEX6 sequencing will identify both mutations in 10-16% of patients. 5-10% of patients will have at least one mutation identified by this panel alone. |
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Analytic Sensitivity: |
Greater than 97% for nucleotides analyzed. All reports will indicate if a certain percentage of nucleotides were not called or were analyzed in a single direction. | |||
| Turn Around Time: | 3 to 4 weeks per test panel, depending on size and complexity | |||
| Fee and CPT Codes: | PEX1
panel 1: $542 for routine testing on blood sample 83891 x 1; 83898 x 3; 83904 x 6; 83909 x 6; 83912 x 1 PEX1 panel 2: $2282 for
routine testing on blood or DNA sample PEX reflex panel; $1454
for routine testing on blood or DNA sample PEX extra panel; $1022
for routine testing on blood or DNA sample PEX6 panel; $1362 for
routine testing on blood sample Please contact the lab to arrange testing for known mutations on blood or prenatal samples. |
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| Special Considerations | ||||
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Arranging Reflex Testing: Because
there are several PEX genes responsible for ZSD, molecular testing can
be complex. You must submit a
Test Instructions form to indicate which reflex tests you desire for
your patient. If no strategy is submitted with the sample, our
default test is PEX1 panel 1 alone.
The suggested test strategy is optimal for
patients with European ethnicity. Please see our
PEX Gene Screen Algorithm for a
general review of the test strategy and for information on patients of
non-European ancestry.
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. |
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| 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. | ||||
Helpful Links |
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| Sample Requirements Requisition and Billing forms Our PEX Gene Screen Algorithm suggesting the optimal test panel order for European and non-European patients. Clinical information on Zellweger Spectrum Disorders Family friendly information: Global Foundation for Peroxisomal Disorders Patient and Family Page for general resources on genetic testing. |
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