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HelpTest ID: PHEGP Phenylalanine Disorders Gene Panel, Varies
Ordering Guidance
The recommended first-tier test for disorders of phenylalanine metabolism is quantitative plasma amino acids (AAQP / Amino Acids, Quantitative, Plasma), as well as neurotransmitters in cerebrospinal fluid and pterin metabolite analysis in blood and urine.
Customization of this panel and single gene analysis for any gene present on this panel is available. For more information see CGPH / Custom Gene Panel, Hereditary, Next-Generation Sequencing, Varies.
Targeted testing for familial variants (also called site-specific or known mutations testing) is available for the genes on this panel. See FMTT / Familial Variant, Targeted Testing, Varies. To obtain more information about this testing option, call 800-533-1710.
Shipping Instructions
Specimen preferred to arrive within 96 hours of collection.
Specimen Required
Patient Preparation: A previous bone marrow transplant from an allogenic donor will interfere with testing. For instructions for testing patients who have received a bone marrow transplant, call 800-533-1710.
Submit only 1 of the following specimens:
Specimen Type: Whole blood
Container/Tube: Lavender top (EDTA) or yellow top (ACD)
Specimen Volume: 3 mL
Collection Instructions:
1. Invert several times to mix blood.
2. Send whole blood specimen in original tube. Do not aliquot.
Specimen Stability Information: Ambient (preferred) 4 days/Refrigerated 14 days
Specimen Type: Skin biopsy
Supplies: Fibroblast Biopsy Transport Media (T115)
Container/Tube: Sterile container with any standard cell culture media (eg, minimal essential media, RPMI 1640). The solution should be supplemented with 1% penicillin and streptomycin.
Specimen Volume: 4-mm punch
Specimen Stability Information: Refrigerated (preferred)/Ambient
Additional Information: A separate culture charge will be assessed under CULFB / Fibroblast Culture for Biochemical or Molecular Testing. An additional 3 to 4 weeks is required to culture fibroblasts before genetic testing can occur.
Specimen Type: Cultured fibroblast
Container/Tube: T-25 flask
Specimen Volume: 2 Flasks
Collection Instructions: Submit confluent cultured fibroblast cells from a skin biopsy from another laboratory. Cultured cells from a prenatal specimen will not be accepted.
Specimen Stability Information: Ambient (preferred)/Refrigerated (<24 hours)
Additional Information: A separate culture charge will be assessed under CULFB / Fibroblast Culture for Biochemical or Molecular Testing. An additional 3 to 4 weeks is required to culture fibroblasts before genetic testing can occur.
Specimen Type: Blood spot
Supplies: Card-Blood Spot Collection (Filter Paper) (T493)
Container/Tube:
Preferred: Collection card (Whatman Protein Saver 903 Paper)
Acceptable: PerkinElmer 226 (formerly Ahlstrom 226) filter paper or blood spot collection card
Specimen Volume: 5 Blood spots
Collection Instructions:
1. An alternative blood collection option for a patient older than 1 year is a fingerstick. For detailed instructions, see How to Collect Dried Blood Spot Samples.
2. Let blood dry on the filter paper at ambient temperature in a horizontal position for a minimum of 3 hours.
3. Do not expose specimen to heat or direct sunlight.
4. Do not stack wet specimens.
5. Keep specimen dry.
Specimen Stability Information: Ambient (preferred)/Refrigerated
Additional Information:
1. Due to lower concentration of DNA yielded from blood spot, it is possible that additional specimen may be required to complete testing.
2. For collection instructions, see Blood Spot Collection Instructions
3. For collection instructions in Spanish, see Blood Spot Collection Card-Spanish Instructions (T777)
4. For collection instructions in Chinese, see Blood Spot Collection Card-Chinese Instructions (T800)
Specimen Type: Saliva
Patient Preparation: Patient should not eat, drink, smoke, or chew gum 30 minutes prior to collection.
Supplies: Saliva Swab Collection Kit (T786)
Specimen Volume: 1 Swab
Collection Instructions: Collect and send specimen per kit instructions.
Specimen Stability Information: Ambient 30 days
Additional Information: Due to lower concentration of DNA yielded from saliva, it is possible that additional specimen may be required to complete testing.
Forms
1. New York Clients-Informed consent is required. Document on the request form or electronic order that a copy is on file. The following documents are available:
-Informed Consent for Genetic Testing (T576)
-Informed Consent for Genetic Testing (Spanish) (T826)
2. Molecular Genetics: Biochemical Disorders Patient Information (T527)
3. If not ordering electronically, complete, print, and send a Biochemical Genetics Test Request (T798) with the specimen.
Useful For
Follow up for abnormal biochemical results suggestive of a phenylalanine disorder
Establishing a molecular diagnosis for patients with phenylalanine disorders
Identifying variants within genes known to be associated with phenylalanine disorders, allowing for predictive testing of at-risk family members
Genetics Test Information
This test utilizes next generation sequencing to detect single nucleotide and copy number variants in 10 genes associated with phenylalanine disorders: DDC, DNAJC12, GCH1, PAH, PCBD1, PTS, QDPR, SLC18A2, SPR, and TH. See Targeted Genes and Methodology Details for Phenylalanine Disorders Gene Panel and Method Description for additional details.
Identification of a disease-causing variant may assist with diagnosis, prognosis, clinical management, familial screening, and genetic counseling for phenylalanine disorders.
Method Name
Sequence Capture and Targeted Next-Generation Sequencing followed by Polymerase Chain Reaction (PCR) and Sanger Sequencing
Reporting Name
Phenylalanine Disorders Gene PanelSpecimen Type
VariesSpecimen Minimum Volume
See Specimen Required
Specimen Stability Information
| Specimen Type | Temperature | Time | Special Container |
|---|---|---|---|
| Varies | Varies | ||
Clinical Information
Hyperphenylalaninemia is a heterogeneous disorder of phenylalanine catabolism caused by a deficiency of any one of 6 enzymes involved in the conversion of phenylalanine to tyrosine.
Phenylketonuria (PKU) is the most frequent inherited disorder of amino acid metabolism (about 1:10,000-1:15,000) and was the first successfully treated inborn error of metabolism and included in newborn screening programs worldwide. It is inherited in an autosomal recessive manner and is caused by a defect in the enzyme phenylalanine hydroxylase (PAH), which converts the essential amino acid phenylalanine to tyrosine. Deficiency of PAH results in decreased levels of tyrosine and an accumulation of phenylalanine in blood and tissues. Untreated, PKU leads to severe brain damage with intellectual impairment, behavior abnormalities, seizures, and spasticity. The level of enzyme activity differentiates classic PKU (PAH activity <1%) from other milder forms; however, all are characterized by increased levels of phenylalanine (hyperphenylalaninemia). Treatment includes the early introduction of a diet low in phenylalanine.
Approximately 2% of patients with hyperphenylalaninemia have a deficiency of tetrahydrobiopterin (BH4), which causes a secondary deficit of the neurotransmitters, dopamine and serotonin. There are 4 autosomal recessive disorders associated with BH4 deficiency plus hyperphenylalaninemia; guanosine triphosphate cyclohydrolase deficiency (GCH1), 6-pyruvoyl tetrahydropterin synthase deficiency (PTS), dihydropteridine reductase deficiency (QDPR), and pterin-4 alpha carbinolamine dehydratase (PCD) deficiency (PCBD1). This group of disorders, with the exception of PCD, is characterized by progressive dystonia, truncal hypotonia, extremity hypertonia, seizures, and intellectual disability though milder presentations exist. PCD has no symptoms other than transient alterations in tone. Treatment may include administration of BH4, L-dopa (and carbidopa) 5-hydroxytryptophan supplements, and a low phenylalanine diet.
Recently, variants in DNAJC12, which encodes a heat-shock protein that interacts with the phenylalanine, tyrosine, and tryptophan hydroxylases to help catalyze the conversion of the substrates to their respective products, has been shown to cause hyperphenylalaninemia, progressive neurodegeneration, and dystonia. Treatment may include early administration of BH4 and/or neurotransmitter precursors.
Related additional disorders of neurotransmitter metabolism include:
-Aromatic l-amino acid decarboxylase (AADC) deficiency, caused by variants in DDC, is an autosomal recessive inborn error in neurotransmitter metabolism that leads to combined serotonin and catecholamine deficiency.
-Patients with dopa-responsive dystonia due to variants in SPR causing sepiapterin reductase deficiency have progressive psychomotor retardation and dystonia.
-Variants in tyrosine hydroxylase (TH) prevent the conversion of L-tyrosine to L-dopa resulting in Segawa syndrome.
-Variants in SLC18A2, a vesicular transporter of dopamine, cause infantile parkinsonism-dystonia-2 (PKDYS2)
Reference Values
An interpretive report will be provided.
Interpretation
All detected alterations are evaluated according to American College of Medical Genetics and Genomics recommendations.(1) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.
Clinical Reference
1. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-424
2. Burgard P, Luo X, Levy HL, Hoffmann GF: Phenylketonuria. In: Sarafoglou K, Hoffmann GF, Roth KS, eds. Pediatric Endocrinology and Inborn Errors of Metabolism. 2nd ed. McGraw-Hill Education; 2017:251-258
3. Blau N, Thony B: Hyperphenylalanemias: Disorders of tetrahydrobiopterin metabolism. In: Sarafoglou K, Hoffmann GF, Roth KS, eds. Pediatric Endocrinology and Inborn Errors of Metabolism. 2nd ed. McGraw-Hill Education; 2017:259-266
4. Anikster Y, Haack TB, Vilboux T, et al. Biallelic mutations in DNAJC12 cause hyperphenylalaninemia, dystonia, and intellectual disability. Am J Hum Genet. 2017;100(2):257-266. doi:10.1016/j.ajhg.2017.01.002
5. OMIM. Johns Hopkins University; Updated March 7, 2024. Accessed March 8, 2024. Available at https://omim.org/
Test Classification
This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. It has not been cleared or approved by the US Food and Drug Administration.CPT Code Information
81405
81406 x 2
81479
88233-Tissue culture, skin, solid tissue biopsy (if appropriate)
88240-Cryopreservation (if appropriate)
81479 (if appropriate for government payers)
LOINC Code Information
| Test ID | Test Order Name | Order LOINC Value |
|---|---|---|
| PHEGP | Phenylalanine Disorders Gene Panel | 105265-3 |
| Result ID | Test Result Name | Result LOINC Value |
|---|---|---|
| 608788 | Test Description | 62364-5 |
| 608789 | Specimen | 31208-2 |
| 608790 | Source | 31208-2 |
| 608791 | Result Summary | 50397-9 |
| 608792 | Result | 82939-0 |
| 608793 | Interpretation | 69047-9 |
| 608794 | Resources | 99622-3 |
| 608795 | Additional Information | 48767-8 |
| 608796 | Method | 85069-3 |
| 608797 | Genes Analyzed | 48018-6 |
| 608798 | Disclaimer | 62364-5 |
| 608799 | Released By | 18771-6 |
Day(s) Performed
Varies
Report Available
14 to 21 daysReflex Tests
| Test ID | Reporting Name | Available Separately | Always Performed |
|---|---|---|---|
| CULFB | Fibroblast Culture for Genetic Test | Yes | No |
Testing Algorithm
For skin biopsy or cultured fibroblast specimens, fibroblast culture testing will be performed at an additional charge. If viable cells are not obtained, the client will be notified.
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