• Test code: 08152
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit

Invitae Hereditary Hemophagocytic Lymphohistiocytosis (HLH) Disorders Panel

Test description

This test analyzes 21 genes that are associated with hereditary hemophagocytic lymphohistiocytosis (HLH). These genes were selected based on the available evidence to date to provide Invitae’s most comprehensive HLH panel.

Genetic testing of these genes may confirm a diagnosis and help guide treatment and management decisions. Identification of a disease-causing variant would also guide testing and diagnosis of at-risk relatives. This test is specifically designed for heritable germline mutations and is not appropriate for the detection of somatic mutations.

If the patient has undergone a bone marrow transplant prior to genetic testing or currently has a hematological malignancy with actively circulating tumor cells, testing a sample type not derived from blood (such as skin biopsy) is warranted. While we do not accept this sample type directly, we can accept gDNA derived from skin or muscle, though deletion/duplication analysis is not guaranteed for gDNA samples because the success rate varies based on sample quality. Please see our Specimen Requirements for more details.

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Primary panel (21 genes)


Gene Disorder Protein name Protein symbol
ADA Adenosine deaminase (ADA) deficiency adenosine deaminase ADA
AP3B1 Hermansky-Pudlak syndrome, type 2 adaptor-related protein complex-3, B1 subunit AP3B1
BLOC1S6 Hermansky-Pudlak syndrome, type 9 palladin PLDN
BTK BTK deficiency Bruton agammaglobulinemia tyrosine kinase BTK
CD27 CD27 deficiency CD27 antigen CD27
IL2RA CD25 deficiency CD25 CD25
IL2RG γc deficiency interleukin receptor common gamma chain gamma-c
ITK lymphoproliferative syndrome 1 (LPFS1) interleukin 2 inducible T-cell kinase ITK
LYST Chediak-Higashi syndrome lysosomal trafficking regulator LYST
MAGT1 X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection, and neoplasia (XMEN) magnesium transporter 1 MAGT1
MVK Mevalonate kinase deficiency mevalonate kinase MVK
PNP Purine nucleoside phosphorylase (PNP) deficiency purine nucleoside phosphorylase PNP
PRF1 Perforin deficiency (FHL2) perforin perforin
RAB27A Griscelli syndrome, type 2 ras-associated protein RAB27A RAB27A
SH2D1A SH2D1A deficiency (XLP1) SH2 domain protein 1A SH2D1A
SLC7A7 lysinuric protein intolerance cationic amino acid transporter 1 SLC7A7
STX11 Syntaxin 11 deficiency, (FHL4) syntaxin 11 STX11
STXBP2 STXBP2 / Munc18-2 deficiency (FHL5) munc18-2 MUNC18-2
UNC13D UNC13D / Munc13-4 deficiency (FHL3) munc13-4 MUNC13-4
WAS Wiskott-Aldrich syndrome, X-linked neutropenia/ myelodysplasia WAS protein WASP
XIAP XIAP deficiency (XLP2) baculoviral IAP-repeat containing protein 4 BIRC4

HLH is a rare lymphoproliferative disorder typically seen in childhood, though some types can have a later age of onset. It is characterized by persistent fever, splenomegaly with cytopenia, hypertriglyceridemia and hypofibrinogenemia, caused by the infiltration of histiocytes with hemophagocytic activity. Cytotoxic T lymphocyte (CTL) toxicity levels are typically associated with the age of onset and pathogenic variant detected. There are two major forms of HLH, a primary and secondary form. Primary forms typically occur in infancy, have primary immunodeficiencies and are familial. Secondary forms are typically associated with infections such as Epstein Barr virus, autoimmune disorders and malignancies. While primary forms of HLH can be controlled by immunotherapy, hematopoietic stem cell transplant is the only known cure.

Determination of an underlying genetic predisposition in an individual with a personal or family history of HLH is critical for the selection of therapy regimens, consideration of bone marrow or stem cell transplant, long-term cancer surveillance and prognosis, and counseling of the individual and their family.

Pathogenic variants in these genes account for an estimated 80% of individuals with primary HLH.

Gene % cases attributed
PRF1 20-30%
SH2D1A Rare
STX11 20% in Kurdish populations
STXBP2 16-20%
UNC13D 20-30%

*Of note, The 253-kb inversion and deep intronic c.118-308C>T variant described in PMID: 21931115 are outside of Invitae’s guaranteed reportable range and therefore may not be analyzed by this test.

The following genes confer an increased risk of HLH in an autosomal recessive inheritance pattern:

The following genes confer an increased risk of HLH in a X-linked inheritance pattern:

This panel may be considered for individuals whose personal and/or family history is suggestive of a hereditary predisposition to HLH, including any of the following:

  • persistent fever with splenomegaly and cytopenia
  • hypertriglyceridemia
  • hypofibrinogenemia
  • hemophagocytosis
  • low NK cell activity
  • high sIL-2R levels
  • a family history of HLH

For proposed recommendations to genetic counseling, testing, and clinical management, please refer to:

  1. Rigaud, S, et al. XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome. Nature. 2006; 444(7115):110-4. PMID: 17080092
  2. Latour, S, Aguilar, C. XIAP deficiency syndrome in humans. Semin. Cell Dev. Biol. 2015; 39:115-23. PMID: 25666262
  3. Pachlopnik, Schmid, J, et al. Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency). Blood. 2011; 117(5):1522-9. PMID: 21119115
  4. Aguilar, C, et al. Characterization of Crohn disease in X-linked inhibitor of apoptosis-deficient male patients and female symptomatic carriers. J. Allergy Clin. Immunol. 2014; 134(5):1131-41.e9. PMID: 24942515
  5. Yang, X, et al. A female patient with incomplete hemophagocytic lymphohistiocytosis caused by a heterozygous XIAP mutation associated with non-random X-chromosome inactivation skewed towards the wild-type XIAP allele. J. Clin. Immunol. 2015; 35(3):244-8. PMID: 25744037
  6. Rezaei, N, et al. X-linked lymphoproliferative syndrome: a genetic condition typified by the triad of infection, immunodeficiency and lymphoma. Br. J. Haematol. 2011; 152(1):13-30. PMID: 21083659
  7. Tangye, SG. XLP: clinical features and molecular etiology due to mutations in SH2D1A encoding SAP. J. Clin. Immunol. 2014; 34(7):772-9. PMID: 25085526
  8. Alkhairy, OK, et al. Novel mutations in TNFRSF7/CD27: Clinical, immunologic, and genetic characterization of human CD27 deficiency. J. Allergy Clin. Immunol. 2015; 136(3):703-712.e10. PMID: 25843314
  9. Gahl, WA, et al. Genetic defects and clinical characteristics of patients with a form of oculocutaneous albinism (Hermansky-Pudlak syndrome). N. Engl. J. Med. 1998; 338(18):1258-64. PMID: 9562579
  10. Huizing, M, Gahl, WA. Disorders of vesicles of lysosomal lineage: the Hermansky-Pudlak syndromes. Curr. Mol. Med. 2002; 2(5):451-67. PMID: 12125811
  11. Toro, J, et al. Dermatologic manifestations of Hermansky-Pudlak syndrome in patients with and without a 16-base pair duplication in the HPS1 gene. Arch Dermatol. 1999; 135(7):774-80. PMID: 10411151
  12. Jung, J, et al. Identification of a homozygous deletion in the AP3B1 gene causing Hermansky-Pudlak syndrome, type 2. Blood. 2006; 108(1):362-9. PMID: 16537806
  13. Linka, RM, et al. Loss-of-function mutations within the IL-2 inducible kinase ITK in patients with EBV-associated lymphoproliferative diseases. Leukemia. 2012; 26(5):963-71. PMID: 22289921
  14. Stepensky, P, et al. IL-2-inducible T-cell kinase deficiency: clinical presentation and therapeutic approach. Haematologica. 2011; 96(3):472-6. PMID: 21109689
  15. Kaplan, J, et al. Chediak-Higashi syndrome. Curr. Opin. Hematol. 2008; 15(1):22-9. PMID: 18043242
  16. Maaloul, I, et al. Chediak-Higashi syndrome presenting in accelerated phase: A case report and literature review. Hematol Oncol Stem Cell Ther. 2015; :None. PMID: 26254864
  17. Karim, MA, et al. Apparent genotype-phenotype correlation in childhood, adolescent, and adult Chediak-Higashi syndrome. Am. J. Med. Genet. 2002; 108(1):16-22. PMID: 11857544
  18. Li, FY, et al. Second messenger role for Mg2+ revealed by human T-cell immunodeficiency. Nature. 2011; 475(7357):471-6. PMID: 21796205
  19. Li, FY, et al. XMEN disease: a new primary immunodeficiency affecting Mg2+ regulation of immunity against Epstein-Barr virus. Blood. 2014; 123(14):2148-52. PMID: 24550228
  20. Ravell, J, et al. X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection, and neoplasia disease: a combined immune deficiency with magnesium defect. Curr. Opin. Pediatr. 2014; 26(6):713-9. PMID: 25313976
  21. Patiroglu, T, et al. A case of XMEN syndrome presented with severe auto-immune disorders mimicking autoimmune lymphoproliferative disease. Clin. Immunol. 2015; 159(1):58-62. PMID: 25956530
  22. Aricò, M, et al. Hemophagocytic lymphohistiocytosis. Report of 122 children from the International Registry. FHL Study Group of the Histiocyte Society. Leukemia. 1996; 10(2):197-203. PMID: 8637226
  23. Ishii, E, et al. Genetic subtypes of familial hemophagocytic lymphohistiocytosis: correlations with clinical features and cytotoxic T lymphocyte/natural killer cell functions. Blood. 2005; 105(9):3442-8. PMID: 15632205
  24. Guandalini, M, et al. Spectrum of imaging appearances in Australian children with central nervous system hemophagocytic lymphohistiocytosis. J Clin Neurosci. 2014; 21(2):305-10. PMID: 24119957
  25. Deiva, K, et al. CNS involvement at the onset of primary hemophagocytic lymphohistiocytosis. Neurology. 2012; 78(15):1150-6. PMID: 22422896
  26. Ding, Q, Yang, LY. Perforin gene mutations in 77 Chinese patients with lymphomas. World J Emerg Med. 2013; 4(2):128-32. PMID: 25215106
  27. Trapani, JA, et al. Human perforin mutations and susceptibility to multiple primary cancers. Oncoimmunology. 2013; 2(4):e24185. PMID: 23734337
  28. Mhatre, S, et al. Unusual clinical presentations of familial hemophagocytic lymphohistiocytosis type-2. J. Pediatr. Hematol. Oncol. 2014; 36(8):e524-7. PMID: 24390453
  29. Rudd, E, et al. Spectrum and clinical implications of syntaxin 11 gene mutations in familial haemophagocytic lymphohistiocytosis: association with disease-free remissions and haematopoietic malignancies. J. Med. Genet. 2006; 43(4):e14. PMID: 16582076
  30. Ménasché, G, et al. Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome. Nat. Genet. 2000; 25(2):173-6. PMID: 10835631
  31. Pachlopnik, Schmid, J, et al. A Griscelli syndrome type 2 murine model of hemophagocytic lymphohistiocytosis (HLH). Eur. J. Immunol. 2008; 38(11):3219-25. PMID: 18991284
  32. Meeths, M, et al. Clinical presentation of Griscelli syndrome type 2 and spectrum of RAB27A mutations. Pediatr Blood Cancer. 2010; 54(4):563-72. PMID: 19953648
  33. Sepulveda, FE, et al. Distinct severity of HLH in both human and murine mutants with complete loss of cytotoxic effector PRF1, RAB27A, and STX11. Blood. 2013; 121(4):595-603. PMID: 23160464
  34. Sperandeo, MP, et al. Lysinuric protein intolerance: update and extended mutation analysis of the SLC7A7 gene. Hum. Mutat. 2008; 29(1):14-21. PMID: 17764084
  35. Sebastio, G, et al. Lysinuric protein intolerance: reviewing concepts on a multisystem disease. Am J Med Genet C Semin Med Genet. 2011; 157C(1):54-62. PMID: 21308987
  36. Ogier, de, Baulny, H, et al. Lysinuric protein intolerance (LPI): a multi organ disease by far more complex than a classic urea cycle disorder. Mol. Genet. Metab. 2012; 106(1):12-7. PMID: 22402328
  37. Torrents, D, et al. Identification of SLC7A7, encoding y+LAT-1, as the lysinuric protein intolerance gene. Nat. Genet. 1999; 21(3):293-6. PMID: 10080182
  38. Tanner, L, et al. Hazards associated with pregnancies and deliveries in lysinuric protein intolerance. Metab. Clin. Exp. 2006; 55(2):224-31. PMID: 16423630
  39. Ishii, E. Hemophagocytic Lymphohistiocytosis in Children: Pathogenesis and Treatment. Front Pediatr. 2016; 4:47. PMID: 27242976

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
ADA NM_000022.2
AP3B1 NM_003664.4
BLOC1S6 NM_012388.3
BTK NM_000061.2
CD27 NM_001242.4
IL2RA NM_000417.2
IL2RG NM_000206.2
ITK NM_005546.3
LYST NM_000081.3
MAGT1 NM_032121.5
MVK NM_000431.3
PNP NM_000270.3
PRF1 NM_001083116.1
RAB27A NM_004580.4
SH2D1A NM_002351.4
SLC7A7 NM_001126106.2
STX11 NM_003764.3
STXBP2 NM_006949.3
UNC13D NM_199242.2
WAS NM_000377.2
XIAP NM_001167.3