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.
ADA AP3B1 BLOC1S6 BTK CD27 IL2RA IL2RG ITK LYST MAGT1 MVK PNP PRF1 RAB27A SH2D1A SLC7A7 STX11 STXBP2 UNC13D WAS XIAP
ADA AP3B1 BLOC1S6 BTK CD27 IL2RA IL2RG ITK LYST MAGT1 MVK PNP PRF1 RAB27A SH2D1A SLC7A7 STX11 STXBP2 UNC13D WAS XIAP
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% |
XIAP | Rare |
*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:
ADA, AP3B1, BLOC1S6, CD27, IL2RA, ITK, LYST, PNP, PRF1, RAB27A, SLC7A7, STX11, STXBP2, and UNC13D
The following genes confer an increased risk of HLH in a X-linked inheritance pattern:
BTK, IL2RG, MAGT1, SH2D1A, WAS, and XIAP
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:
For proposed recommendations to genetic counseling, testing, and clinical management, please refer to:
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 |