Familial Hemophagocytic Lymphohistiocytosis, X-linked Lymphoproliferative Disease via the XIAP/BIRC4 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 | |
|---|---|---|---|---|---|
| 9989 | XIAP | 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 numerous organs. Clinical manifestations include fever, hepatosplenomegaly, pancytopenia, hemophagocytosis, severely attenuated or absent NK cell function, elevated iron levels, and elevated soluble CD25 (Henter et al. 2007). Familial (primary) HLH (FHL) and sporadic (secondary) HLH are clinically similar, and both types are often, but not always, triggered by viral infections (e.g. Epstein-Barr virus, EBV), rheumatic disorders, and malignancies. 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. 1996; Janka 1983). Though rare, cases of late-onset, adult FHL have been reported in patients ranging in age from their twenties to sixties (Allen et al. 2001; Clementi et al. 2002; Nagafuji et al. 2007). Males with HLH may have a related condition defined as X-linked Lymphoproliferative Disorder (XLP) that may include gammaglobulinemia, and lymphoma (Coffey et al. 1998; Aricio et al. 2001; Rigaud et al. 2006; Booth et al. 2011).
Genetics
FHL is an autosomal recessive or X-linked disorder. Mutations in the PRF1, UNC13D, STX11, and STXBP2 genes cause FHL Types 2, 3, 4, and 5, respectively. X-linked HLH is associated with mutations in the genes XIAP and SH2D1A (X-linked lymphoproliferative disorder). Other disorders associated with HLH include Griscelli syndrome (RAB27A gene), Chediak-Higashi syndrome (LYST gene), and Hermansky-Pudlak syndrome type II (AP3B1 gene). The protein products of UNC13D, STX11, STXBP2, LYST and RAB27A help regulate cytolytic granule biogenesis and fusion with CTL or NK cell plasma membranes along the immunological synapse during granzyme secretion (Tchernev et al. 2002; Jordan et al. 2011). The protein product of PRF1 plays a role in pore formation on target cell plasma membranes required for granzyme-meditated apoptosis (Jordan et al. 2011). SH2D1A encodes SAP (SLAM associated protein) which plays a role in lymphocyte signal transduction initiated by surface immune receptors (Sayos et al. 1998), and XIAP (X-linked inhibitor of apoptosis) encodes an inhibitor of multiple caspases (Deveraux et al. 1997).
Mutations in PRF1 account for 20-40% of all FHL cases and mutations in UNC13D, STX11, and STXBP2 account for approximately 20-25%, 14%, and 10% of FHL cases, respectively (reviewed in Gholam et al. Clinical and Experimental Immunology 163:271, 2011). Most cases (~60%) of XLP / X-linked HLH are caused by mutations in the SH2D1A gene (Coffey et al. 1998; Shinozaki et al. 2002). XLP Patients harboring SH2D1A mutations may have a more severe phenotype than patients harboring mutations in XIAP and also have an increased risk of developing lymphoma (Booth et al. 2011). Causative mutations in the XIAP gene are primarily missense/nonsense mutations, splice-site mutations, and small insertions and deletions. Large, multi-exon deletions in XIAP have also been reported.
Clinical Sensitivity - Sequencing with CNV PGxome
Mutations in XIAP are a rare cause of FHL (< 10%).
Large deletions in XIAP have been reported in FHL patients, but they make up < 10% of all reported XIAP mutations.
Testing Strategy
This test provides full coverage of all coding exons of the XIAP 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 including Griscelli syndrome (RAB27A), Chediak-Higashi syndrome (LYST/CHS1) and Hermansky Pudlak syndrome type II (AP3B1), and individuals with a family history of FHL. Conversely, FHL patients who test negative for PRF1, UNC13D, STX11, STXBP2, SH2D1A, and XIAP may be candidates for Griscelli syndrome, Chediak-Higashi syndrome, and Hermansky Pudlak syndrome type II DNA testing.
Patients with clinical features of FHL or FHL-related disorders including Griscelli syndrome (RAB27A), Chediak-Higashi syndrome (LYST/CHS1) and Hermansky Pudlak syndrome type II (AP3B1), and individuals with a family history of FHL. Conversely, FHL patients who test negative for PRF1, UNC13D, STX11, STXBP2, SH2D1A, and XIAP may be candidates for Griscelli syndrome, Chediak-Higashi syndrome, and Hermansky Pudlak syndrome type II DNA testing.
Gene
| Official Gene Symbol | OMIM ID |
|---|---|
| XIAP | 300079 |
| Inheritance | Abbreviation |
|---|---|
| Autosomal Dominant | AD |
| Autosomal Recessive | AR |
| X-Linked | XL |
| Mitochondrial | MT |
Disease
| Name | Inheritance | OMIM ID |
|---|---|---|
| Lymphoproliferative Syndrome, X-Linked, 2 | XL | 300635 |
Related Tests
Citations
- Allen M, Fusco C De, Legrand F, Clementi R, Conter V, Danesino C, Janka G, Aricò M. 2001. Familial hemophagocytic lymphohistiocytosis: how late can the onset be? haematologica 86: 499–503. PubMed ID: 11410413
- Arico M, Imashuku S, Clementi R, Hibi S, Teramura T, Danesino C, Haber DA, Nichols KE. 2001. Hemophagocytic lymphohistiocytosis due to germline mutations inSH2D1A, the X-linked lymphoproliferative disease gene. Blood 97: 1131–1133. PubMed ID: 11159547
- 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
- Booth C, Gilmour KC, Veys P, Gennery AR, Slatter MA, Chapel H, Heath PT, Steward CG, Smith O, O’Meara A, Kerrigan H, Mahlaoui N, et al. 2011. X-linked lymphoproliferative disease due to SAP/SH2D1A deficiency: a multicenter study on the manifestations, management and outcome of the disease. Blood 117: 53–62. PubMed ID: 20926771
- Clementi R. 2002. Adult onset and atypical presentation of hemophagocytic lymphohistiocytosis in siblings carrying PRF1 mutations. Blood 100: 2266–2266. PubMed ID: 12229880
- Coffey AJ, Brooksbank RA, Brandau O, Oohashi T, Howell GR, Bye JM, Cahn AP, Durham J, Heath P, Wray P, Pavitt R, Wilkinson J, et al. 1998. Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene. Nat Genet 20: 129–135. PubMed ID: 9771704
- Deveraux QL, Takahashi R, Salvesen GS, Reed JC. 1997. X-linked IAP is a direct inhibitor of cell-death proteases. Nature 388: 300–304. PubMed ID: 9230442
- Gholam C, Grigoriadou S, Gilmour KC, Gaspar HB. 2011. Familial haemophagocytic lymphohistiocytosis: advances in the genetic basis, diagnosis and management: Familial haemophagocytic lymphohistiocytosis. Clinical & Experimental Immunology 163: 271–283. PubMed ID: 21303357
- 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
- Jordan MB, Allen CE, Weitzman S, Filipovich AH, McClain KL. 2011. How I treat hemophagocytic lymphohistiocytosis. Blood 118: 4041–4052. PubMed ID: 21828139
- Nagafuji K, Nonami A, Kumano T, Kikushige Y, Yoshimoto G, Takenaka K, Shimoda K, Ohga S, Yasukawa M, Horiuchi H. 2007. Perforin gene mutations in adult-onset hemophagocytic lymphohistiocytosis. Haematologica 92: 978–981. PubMed ID: 17606450
- Rigaud S, Fondanèche M-C, Lambert N, Pasquier B, Mateo V, Soulas P, Galicier L, Deist F Le, Rieux-Laucat F, Revy P, Fischer A, Saint Basile G de, et al. 2006. XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome. Nature 444: 110–114. PubMed ID: 17080092
- Sayos J, Wu C, Morra M, Wang N, Zhang X, Allen D, Schaik S Van, Notarangelo L, Geha R, Roncarolo MG. 1998. The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM. Nature 395: 462–469. PubMed ID: 9774102
- Shinozaki K, Kanegane H, Matsukura H, Sumazaki R, Tsuchida M, Makita M, Kimoto Y, Kanai R, Tsumura K, Kondoh T. 2002. Activation-dependent T cell expression of the X-linked lymphoproliferative disease gene product SLAM-associated protein and its assessment for patient detection. International immunology 14: 1215–1223. PubMed ID: 12356686
- Tchernev VT, Mansfield TA, Giot L, Kumar AM, Nandabalan K, Li Y, Mishra VS, Detter JC, Rothberg JM, Wallace MR. 2002. The Chediak-Higashi protein interacts with SNARE complex and signal transduction proteins. Molecular Medicine 8: 56-64. PubMed ID: 11984006
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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