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Familial Hemophagocytic Lymphohistiocytosis (FHL) Panel

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
ADA 81479,81479
AP3B1 81479,81479
BLOC1S6 81479,81479
BTK 81406,81479
CD27 81479,81479
CD70 81479,81479
HAVCR2 81479,81479
IL2RA 81479,81479
IL2RG 81405,81479
ITK 81479,81479
LYST 81479,81479
MAGT1 81479,81479
MEFV 81404,81479
MVK 81479,81479
NLRC4 81479,81479
NLRP3 81479,81479
PNP 81479,81479
PRF1 81479,81479
RAB27A 81479,81479
RHOG 81479,81479
SH2D1A 81404,81403
SLC7A7 81479,81479
STX11 81479,81479
STXBP2 81479,81479
TNFRSF1A 81479,81479
UNC13D 81479,81479
WAS 81406,81479
XIAP 81479,81479
ZNFX1 81479,81479
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
10377Genes x (29)81479 81403(x1), 81404(x2), 81405(x1), 81406(x2), 81479(x52) $990 Order Options and Pricing

Pricing Comments

We are happy to accommodate requests for testing single genes in this panel or a subset of these genes. The price will remain the list price. If desired, free reflex testing to remaining genes on panel is available. Alternatively, a single gene or subset of genes can also be ordered via our Custom Panel tool.

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).

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.

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • Siwu Peng, PhD

Clinical Features and Genetics

Clinical Features

Hemophagocytic Lymphohistiocytosis (HLH) is a rapidly progressing, hyperinflammatory condition 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. PubMed ID: 16937360). Familial (primary) HLH (FHL) and sporadic (secondary) HLH are clinically similar, and both types are often, but not always, triggered by viral infections (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. PubMed ID: 8637226; Janka. 1983. PubMed ID: 6354720). 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. PubMed ID: 11410413; Clementi et al. 2002. PubMed ID: 12229880; Nagafuji et al. 2007. PubMed ID: 17606450). Males with HLH may have X-linked Lymphoproliferative Disorder (XLP) that may include gammaglobulinemia, and lymphoma (Coffey et al. 1998. PubMed ID: 9771704; Arico et al. 2001. PubMed ID: 11159547; Rigaud et al. 2006. PubMed ID: 17080092; Booth et al. 2011. PubMed ID: 20926771).

Genetics

FHL is primarily an autosomal recessive or X-linked disorder, though a few autosomal dominant conditions are associated with FHL (see below). Over 75% of FHL cases can be attributed to pathogenic variants in one of six genes: PRF1 (FHL Type 2), UNC13D (FHL Type 3), STX11 (FHL Type 4), STXBP2 (FHL Type 5), and the XIAP and SH2D1A genes (both are associated with X-linked FHL). Pathogenic variants in PRF1 account for 20-40% of all FHL cases and pathogenic variants in UNC13D, STX11, and STXBP2 account for approximately 20-25%, 14%, and 10% of FHL cases, respectively (Gholam et al. 2011. PubMed ID: 21303357). Around 60% of X-linked FHL is caused by pathogenic variants in the SH2D1A gene (Coffey et al. 1998. PubMed ID: 9771704; Gilmour et al. 2000. PubMed ID: 10898506; Yin et al. 1999. PubMed ID: 10598819; Nichols et al. 1998. PubMed ID: 9811875).

Several other disorders and genes are associated with FHL including the following: Griscelli syndrome (RAB27A; Meschede et al. 2008. PubMed ID: 19030707), Chediak-Higashi syndrome (LYST; Karim et al. 2002. PubMed ID: 11857544), Hermansky-Pudlak syndrome (AP3B1; Clark et al. 2003. PubMed ID: 14566336, BLOC1S6; Badolato et al. 2012. PubMed ID: 22461475), Lymphoproliferative syndrome 1 (ITK; Linka et al. 2012. PubMed ID: 22289921), Immunodeficiency 41 with lymphoproliferations and autoimmunity (IL2RA; Goudy et al. 2013. PubMed ID: 23416241), Immunodeficiency due to purine nucleoside phosphorylase deficiency (PNP; Al-Mousa et al. 2016. PubMed ID: 26915675), X-linked immunodeficiency (IL2RG; Puck et al. 1997. PubMed ID: 9058718, MAGT1; Li et al. 2011. PubMed ID: 21796205), Lymphoproliferative syndrome 2 (CD27; Salzer et al. 2013. PubMed ID: 22801960), Lysinuric protein intolerance (SLC7A7; Font-Llitjos et al. 2009. PubMed ID: 18716612), severe combined immunodeficiency (ADA; Valerio et al. 1986. PubMed ID: 3007108), Wiskott-Aldrich syndrome (WAS; Jin et al. 2004. PubMed ID: 15284122), Hyper-IgD syndrome (MVK; Mandey et al. 2006. PubMed ID: 16835861), X-linked Agammaglobulinemia (BTK; Conley et al. 1998. PubMed ID: 9545398), combined immunodeficiency (CD70; Izawa et al. 2017. PubMed ID: 28011863), familial Mediterranean fever (MEFV; French FMF Consortium. 1997. PubMed ID: 9288094), Autoinflamation (autosomal recessive and autosomal dominant inheritance, NLRC4; Canna et al. 2014. PubMed ID: 25217959), Multisystem inflammatory disease (autosomal dominant inheritance, NLRP3; Jesus et al. 2008. PubMed ID: 18080732), Periodic fever (autosomal dominant inheritance, TNFRSF1A; Cantarini et al. 2012. PubMed ID: 22884554).

Causative variants in the FHL-associated genes are primarily missense/nonsense variants, splice-site variants, and small insertions and deletions. Large, multi-exon and whole gene deletions have been reported in some of the most common FHL associated genes including STX11 and RAB27A, and particularly the X-linked genes XIAP and SH2D1A in which deletions make up ~ 17% and 20% of the unique reported pathogenic variants, respectively. Large deletions and/or duplications have also been reported in the AP3B1, IL2RG, MAGT1, SLC7A7, ADA, WAS, MVK, and BTK genes and generally make up a small fraction of the unique pathogenic variants reported for each gene.

This test does include analysis of a known pathogenic inversion involving the UNC13D gene that was observed in 7% of FHL patients in one report (Meeths et al. 2011. PubMed ID: 21931115; Qian et al. 2014. PubMed ID: 24470399).

See individual gene test descriptions for information on molecular biology of gene products.

Clinical Sensitivity - Sequencing with CNV PGxome

Over 75% of Familial Hemophagocytic Lymphohistiocytosis (FHL) cases can be attributed to pathogenic variants in one of six genes: PRF1 (FHL Type 2), UNC13D (FHL Type 3), STX11 (FHL Type 4), STXBP2 (FHL Type 5), and the XIAP and SH2D1A genes (both are associated with X-linked FHL). Pathogenic variants in PRF1 account for 20-40% of all FHL cases and pathogenic variants in UNC13D, STX11, and STXBP2 account for approximately 20-25%, 14%, and 10% of FHL cases, respectively (Gholam et al. 2011. PubMed ID: 21303357). Around 60% of X-linked FHL is caused by variants in the SH2D1A gene (Coffey et al. 1998. PubMed ID: 9771704; Gilmour et al. 2000. PubMed ID: 10898506; Yin et al. 1999. PubMed ID: 10598819; Nichols et al. 1998. PubMed ID: 9811875).

Large, multi-exon and whole gene deletions have been reported in some of the most common FHL associated genes, including STX11 and RAB27A, and particularly the X-linked genes XIAP and SH2D1A in which deletions make up ~ 17% and 20% of the unique reported pathogenic variants, respectively. Large deletions and/or duplications have also been reported in the AP3B1, IL2RG, MAGT1, SLC7A7, ADA, WAS, MVK, and BTK genes and generally make up a small fraction of the unique pathogenic variants reported for each gene.

Testing Strategy

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 99.8% coverage of all coding exons of the genes 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 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 or family history of FHL or FHL-related disorders including lymphoproliferative syndromes and immunodeficiencies.

Related Test

Name
PGxome®

Citations

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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2) Select Additional Test Options

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