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
10377 ADA 81479,81479 Order Options and Pricing
AP3B1 81479,81479
BLOC1S6 81479,81479
BTK 81406,81479
CD27 81479,81479
CD70 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
SH2D1A 81404,81403
SLC7A7 81479,81479
STX11 81479,81479
STXBP2 81479,81479
TNFRSF1A 81479,81479
UNC13D 81479,81479
WAS 81406,81479
XIAP 81479,81479
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
10377Genes x (26)81479 81403, 81404, 81405, 81406, 81479 $890 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 PGxome Custom Panel tool.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

For Reflex to PGxome pricing click here.

Turnaround Time

18 days on average for standard orders or 14 days on average for STAT orders.

Once a specimen has started the testing process in our lab, the most accurate prediction of TAT will be displayed in the myPrevent portal as an Estimated Report Date (ERD) range. We calculate the ERD for each specimen as testing progresses; therefore the ERD range may differ from our published average TAT. View 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

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 100% 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.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

Indications for Test

Patients with clinical features or family history of FHL or FHL-related disorders including lymphoproliferative syndromes and immunodeficiencies.

Genes

Official Gene Symbol OMIM ID
ADA 608958
AP3B1 603401
BLOC1S6 604310
BTK 300300
CD27 186711
CD70 602840
IL2RA 147730
IL2RG 308380
ITK 186973
LYST 606897
MAGT1 300715
MEFV 608107
MVK 251170
NLRC4 606831
NLRP3 606416
PNP 164050
PRF1 170280
RAB27A 603868
SH2D1A 300490
SLC7A7 603593
STX11 605014
STXBP2 601717
TNFRSF1A 191190
UNC13D 608897
WAS 300392
XIAP 300079
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Test

Name
PGxome®

Citations

  • Al-Mousa et al. 2016. PubMed ID: 26915675
  • Allen et al. 2001. PubMed ID: 11410413
  • Aric├▓ et al. 1996. PubMed ID: 8637226
  • Arico et al. 2001. PubMed ID: 11159547
  • Badolato et al. 2012. PubMed ID: 22461475
  • Booth et al. 2011. PubMed ID: 20926771
  • Canna et al. 2014. PubMed ID: 25217959
  • Cantarini et al. 2012. PubMed ID: 22884554
  • Clark et al. 2003. PubMed ID: 14566336
  • Clementi et al. 2002. PubMed ID: 12229880
  • Coffey et al. 1998. PubMed ID: 9771704
  • Conley et al. 1998. PubMed ID: 9545398
  • Font-Llitjos et al. 2009. PubMed ID: 18716612
  • French FMF Consortium. 1997. PubMed ID: 9288094
  • Gholam et al. 2011. PubMed ID: 21303357
  • Gilmour et al. 2000. PubMed ID: 10898506
  • Goudy et al. 2013. PubMed ID: 23416241
  • Henter et al. 2007. PubMed ID: 16937360
  • Izawa et al. 2017. PubMed ID: 28011863
  • Janka. 1983. PubMed ID: 6354720
  • Jesus et al. 2008. PubMed ID: 18080732
  • Jin et al. 2004. PubMed ID: 15284122
  • Karim et al. 2002. PubMed ID: 11857544
  • Li et al. 2011. PubMed ID: 21796205
  • Linka et al. 2012. PubMed ID: 22289921
  • Mandey et al. 2006. PubMed ID: 16835861
  • Meeths et al. 2011. PubMed ID: 21931115
  • Meschede et al. 2008. PubMed ID: 19030707
  • Nagafuji et al. 2007. PubMed ID: 17606450
  • Nichols et al. 1998. PubMed ID: 9811875
  • Puck et al. 1997. PubMed ID: 9058718
  • Qian et al. 2014. PubMed ID: 24470399
  • Rigaud et al. 2006. PubMed ID: 17080092
  • Salzer et al. 2013. PubMed ID: 22801960
  • Valerio et al. 1986. PubMed ID: 3007108
  • Yin et al. 1999. PubMed ID: 10598819

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.

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


Specimen Types

Specimen Requirements and Shipping Details

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ORDER OPTIONS

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2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

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