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Familial Hemophagocytic Lymphohistiocytosis-Type 5 (FHL5) via the STXBP2 Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
STXBP2 81479 81479,81479 $990
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
11723STXBP281479 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.


Genetic Counselors


  • Siwu Peng, PhD

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). Late-onset FHL cases (i.e. teens or twenties) have also been reported (Allen et al. Haematologica 86:499-503, 2001).


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 have been found throughout the STXBP2 gene comprising primarily missense or nonsense, splice-site, and small deletions or insertions(zur Stadt et al. Am J Hum Genet 85:482-492, 2009; Côte et al. J Clin Invest 119:3765-3773, 2009; Meeths et al. Blood 2010). STXBP2 encodes Munc18-2, a regulatory protein involved in SNARE-mediated granule secretion in NK cells and CTLs. In patients with FHL5, missense variants in STXBP2 disrupt the ability of Munc18-2 to interact with syntaxin 11, a SNARE protein mutated in FHL4. Variants in FHL3, 4, and 5 genes result in defective NK cell and CTL degranulation whereas variants in the FHL2 gene directly affect a lytic granule cargo molecule.

Clinical Sensitivity - Sequencing with CNV PGxome

FHL5 accounts for ~16% of FHL cases.

Testing Strategy

This test provides full coverage of all coding exons of the STXBP2 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 PRF1, UNC13D, and STX11. 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 STXBP2.


Official Gene Symbol OMIM ID
STXBP2 601717
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Hemophagocytic lymphohistiocytosis, Familial, 5 613101


  • 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
  • Cote, M., et.al. (2009). "Munc18-2 deficiency causes familial hemophagocytic lymphohistiocytosis type 5 and impairs cytotoxic granule exocytosis in patient NK cells." J Clin Invest 119(12): 3765-73. PubMed ID: 19884660
  • Fisman, D. N. (2000). "Hemophagocytic syndromes and infection." Emerg Infect Dis 6(6): 601-8. PubMed ID: 11076718
  • 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
  • Meeths, M., et.al. (2010). "Spectrum of clinical presentations in familial hemophagocytic lymphohistiocytosis (FHL) type 5 patients with mutations in STXBP2." Blood. PubMed ID: 20558610
  • zur Stadt, U., et.al. (2009). "Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused by mutations in Munc18-2 and impaired binding to syntaxin 11." Am J Hum Genet 85(4): 482-92. PubMed ID: 19804848


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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Note: acceptable specimen types are whole blood and DNA from whole blood only.
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