Familial Hemophagocytic Lymphohistiocytosis-Type 2 (FHL2) via the PRF1 Gene
Summary and Pricing 
Test Method
Exome Sequencing with CNV Detection
| Test Code | Test Copy Genes | Test CPT Code | Gene CPT Codes Copy CPT Code | Base Price | |
|---|---|---|---|---|---|
| 8817 | PRF1 | 81479 | 81479,81479 | $990 | Order Options and Pricing |
Pricing Comments
Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information. If the Sanger option is selected, CNV detection may be ordered through Test #600.
An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.
Click here for costs to reflex to whole PGxome (if original test is on PGxome Sequencing platform).
Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing platform).
The Sanger Sequencing method for this test is NY State approved.
For Sanger Sequencing click here.Turnaround Time
3 weeks on average for standard orders or 2 weeks on average for STAT orders.
Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.
Targeted Testing
For ordering sequencing of targeted known variants, go to our Targeted Variants page.
Clinical Features and Genetics
Clinical Features
Hemophagocytic lymphohistiocytosis (HLH) is a rapidly progressing, hyperinflammatory syndrome in which activated T cells and macrophages infiltrate the liver, spleen, bone marrow, and central nervous system. Clinical manifestations include fever, hepatosplenomegaly, pancytopenia, hemophagocytosis, high triglyceride and ferritin levels, hypofibrinogenemia, severely attenuated or absent NK cell function, and high soluble CD25 (Henter et al. Pediatr Blood Cancer 48:124-131, 2007). Familial HLH (FHL) and sporadic (secondary) HLH are clinically indistinguishable and may be triggered by viral infections, rheumatic disorders, and malignancies (Fisman. Emerging Infect Dis 6:601-608, 2000). The incidence of FHL is approximately 1 in 50,000 live births with 70-80% of patients showing clinical symptoms during infancy (Aricò et al. Leukemia 10:197-203, 1996; Janka. Eur J Pediatr 140:221-230, 1983). Cases of late-onset FHL (i.e. teens or twenties) have also been reported (Allen et al. Haematologica 86:499-503, 2001).
Genetics
FHL is an autosomal recessive disorder. Variants in the PRF1, UNC13D, STX11, and STXBP2 genes cause FHL types 2 (OMIM 603553), 3 (OMIM 608898), 4 (OMIM 603552), and 5 (OMIM 613101), respectively. Variants in these four genes account for ~ 70% of FHL cases. Though genetically heterogeneous, FHL is clinically homogeneous. Causative variants in PRF1 have been identified throughout the coding region (exons 2 and 3) and are primarily missense or nonsense variants, but small deletions and insertions have also been reported (Stepp et al. Science 286:1957-1959, 1999; Clementi et al. J Med Genet 38:643-646, 2001; Göransdotter et al. Am J Hum Genet 68:590-597, 2001; Lee et al. J Pediatr 149:134-137, 2006). No single predominant PRF1 variant has been identified, but some appear more commonly in certain patient populations. For example, PRF1 variants account for ~50% of FHL patients of African American ancestry, and all of these patients have the c.50delT variant (Lee et al. J Pediatr 149:134-137, 2006; Molleran Lee et al. J Med Genet 1:137-144, 2004). Similarly, a p.W374* variant appears at a high frequency in Turkish patients (Stadt et al. Hum Mutat 27:62-68, 2006). PRF1 encodes perforin, a component of lytic granules important for the release of granzyme B from CTLs to target cells where it induces apoptosis.
Clinical Sensitivity - Sequencing with CNV PGxome
FHL2 accounts for 20-50% of all FHL cases.
Testing Strategy
This test provides full coverage of all coding exons of the PRF1 gene 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 full 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).
Indications for Test
Patients with clinical features of FHL or FHL-related disorders, individuals with a family history of FHL, and FHL patients who test negative for variants in UNC13D, STX11, and STXBP2. In addition, Griscelli syndrome (GS2) (RAB27A), Chediak-Higashi syndrome (CHS) (LYST/CHS1), and Hermansky Pudlak syndrome (HPS2) (AP3B1) patients who test negative for those genes may be candidates for PRF1 and additional FHL gene testing. Conversely, FHL patients who test negative for PRF1, UNC13D, STX11, and STXBP2 may be candidates for GS2, CHS, and HPS2 DNA testing. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in PRF1.
Patients with clinical features of FHL or FHL-related disorders, individuals with a family history of FHL, and FHL patients who test negative for variants in UNC13D, STX11, and STXBP2. In addition, Griscelli syndrome (GS2) (RAB27A), Chediak-Higashi syndrome (CHS) (LYST/CHS1), and Hermansky Pudlak syndrome (HPS2) (AP3B1) patients who test negative for those genes may be candidates for PRF1 and additional FHL gene testing. Conversely, FHL patients who test negative for PRF1, UNC13D, STX11, and STXBP2 may be candidates for GS2, CHS, and HPS2 DNA testing. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in PRF1.
Gene
| Official Gene Symbol | OMIM ID |
|---|---|
| PRF1 | 170280 |
| Inheritance | Abbreviation |
|---|---|
| Autosomal Dominant | AD |
| Autosomal Recessive | AR |
| X-Linked | XL |
| Mitochondrial | MT |
Disease
| Name | Inheritance | OMIM ID |
|---|---|---|
| Hemophagocytic Lymphohistiocytosis, Familial, 2 | AR | 603553 |
Related Tests
Citations
- Allen, M., et.al. (2001). "Familial hemophagocytic lymphohistiocytosis: how late can the onset be?." Haematologica 86(5): 499-503. PubMed ID: 11410413
- Arico M, Janka G, Fischer A, Henter JI, Blanche S, Elinder G, Martinetti M, Rusca MP. 1996. Hemophagocytic lymphohistiocytosis. Report of 122 children from the International Registry. FHL Study Group of the Histiocyte Society. Leukemia 10: 197–203. PubMed ID: 8637226
- Clementi, R., et.al. (2001). "Six novel mutations in the PRF1 gene in children with haemophagocytic lymphohistiocytosis." J Med Genet 38(9): 643-6. PubMed ID: 11565555
- Fisman, D. N. (2000). "Hemophagocytic syndromes and infection." Emerg Infect Dis 6(6): 601-8. PubMed ID: 11076718
- Goransdotter Ericson, K., et.al. (2001). "Spectrum of perforin gene mutations in familial hemophagocytic lymphohistiocytosis." Am J Hum Genet 68(3): 590-7. PubMed ID: 11179007
- Henter J-I, Horne A, Aricó M, Egeler RM, Filipovich AH, Imashuku S, Ladisch S, McClain K, Webb D, Winiarski J, Janka G, for the Histiocyte Society. 2007. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatric Blood & Cancer 48: 124–131. PubMed ID: 16937360
- Janka GE. 1983. Familial hemophagocytic lymphohistiocytosis. Eur. J. Pediatr. 140: 221–230. PubMed ID: 6354720
- Lee, S. M., et.al. (2006). "Patients of African ancestry with hemophagocytic lymphohistiocytosis share a common haplotype of PRF1 with a 50delT mutation." J Pediatr 149(1): 134-7. PubMed ID: 16860143
- Molleran Lee, S., et.al. (2004). "Characterisation of diverse PRF1 mutations leading to decreased natural killer cell activity in North American families with haemophagocytic lymphohistiocytosis." J Med Genet 41(2): 137-44. PubMed ID: 14757862
- Stepp, S. E., et.al. (1999). "Perforin gene defects in familial hemophagocytic lymphohistiocytosis." Science 286(5446): 1957-9. PubMed ID: 10583959
- Zur Stadt, U., et.al. (2006). "Mutation spectrum in children with primary hemophagocytic lymphohistiocytosis: molecular and functional analyses of PRF1, UNC13D, STX11, and RAB27A." Hum Mutat 27(1): 62-8. PubMed ID: 16278825
Ordering/Specimens
Ordering Options
We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.
myPrevent - Online Ordering
- The test can be added to your online orders in the Summary and Pricing section.
- Once the test has been added log in to myPrevent to fill out an online requisition form.
- PGnome sequencing panels can be ordered via the myPrevent portal only at this time.
Requisition Form
- A completed requisition form must accompany all specimens.
- Billing information along with specimen and shipping instructions are within the requisition form.
- All testing must be ordered by a qualified healthcare provider.
For Requisition Forms, visit our Forms page
If ordering a Duo or Trio test, the proband and all comparator samples are required to initiate testing. If we do not receive all required samples for the test ordered within 21 days, we will convert the order to the most effective testing strategy with the samples available. Prior authorization and/or billing in place may be impacted by a change in test code.
Specimen Types
Specimen Requirements and Shipping Details
PGxome (Exome) Sequencing Panel
PGnome (Genome) Sequencing Panel
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ORDER OPTIONS
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