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Familial Hemophagocytic Lymphohistiocytosis-Type 3 (FHL3) via the UNC13D Inversion

Summary and Pricing

Test Method

Targeted Deletion Testing via PCR
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
2050 UNC13D 81479 81479 $250 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
2050UNC13D81479 81479 $250 Order Options and Pricing

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

Turnaround Time

18 days on average for standard orders or 14 days 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.

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. Both types may be 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. 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). Most of the FHL genes encode proteins that help regulate lytic granule targeting, docking, and membrane fusion during CTL and NK cell degranulation. PRF1 encodes a primary component of lytic granule cargo involved directly in membrane disruption of target cells at the immunological synapse (Gholam et al. 2011. PubMed ID: 21303357).  

Pathogenic variants are located throughout the UNC13D gene and comprise primarily missense/nonsense variants, splice-site variants, and small insertions and deletions. Most variants are inherited from parental carriers; de novo variants are rare. Large copy number variants are rare with only one large duplication having been reported to date (Feldmann et al. 2003. PubMed ID: 14622600; Yamamoto et al. 2004. PubMed ID: 15466010; Zur Stadt et al. 2006. PubMed ID: 16278825; Hiejima et al. 2018. PubMed ID: 29596912).

UNC13D encodes the Munc13-4 protein which regulates SNARE-mediated lytic granule exocytosis in CTLs and NK cells (Feldmann et al. 2003. PubMed ID: 14622600). UNC13D has been cited as a nonessential gene for growth of human tissue culture cells (Online Gene Essentiality, ogee.medgenius.info).

Mouse models in which Unc13d is absent have shown a complete loss of platelet dense granule secretion and attenuated platelet aggregation.  Mice lacking Unc13d also had prolonged bleeding times which is consistent with the Unc13d gene product serving a critical role during proper platelet function (Ren et al. 2010. PubMed ID: 20435885).

This test involves 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). This test employs custom PCR reactions to detect a 253-kb inversion involving Alu elements in intron 30 and in the 3' region downstream of the UNC13D gene. This inversion abolishes UNC13D protein expression and is known to cause disease when present with another pathogenic UNC13D gene variant. 

Clinical Sensitivity - Targeted Deletion

The UNC13D inversion was identified in 7% of FHL patients in one report (Meeths et al. 2011. PubMed ID: 21931115; Qian et al. 2014. PubMed ID: 24470399).

Testing Strategy

This test is performed using custom PCR primer probesets to amplify regions within and surrounding the 253-kb inversion sequence. Appropriate positive and negative controls are used in order to confirm the presence of the inversion in carriers and when present in the homozygous state in affected individuals. 

Indications for Test

Patients with clinical features or family history of FHL or FHL-related disorders including lymphoproliferative syndromes and immunodeficiencies are candidates. Targeted testing is indicated for family members of patients who have known pathogenic variants in UNC13D. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in UNC13D.  

Gene

Official Gene Symbol OMIM ID
UNC13D 608897
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Hemophagocytic Lymphohistiocytosis, Familial, 3 AR 608898

Related Test

Name
Familial Hemophagocytic Lymphohistiocytosis (FHL) Panel

Citations

  • Allen et al. 2001. PubMed ID: 11410413
  • Aric├▓ et al. 1996. PubMed ID: 8637226
  • Arico et al. 2001. PubMed ID: 11159547
  • Booth et al. 2011. PubMed ID: 20926771
  • Clementi et al. 2002. PubMed ID: 12229880
  • Coffey et al. 1998. PubMed ID: 9771704
  • Feldmann et al. 2003. PubMed ID: 14622600
  • Gholam et al. 2011. PubMed ID: 21303357
  • Gilmour et al. 2000. PubMed ID: 10898506
  • Henter et al. 2007. PubMed ID: 16937360
  • Hiejima et al. 2018. PubMed ID: 29596912
  • Janka. 1983. PubMed ID: 6354720
  • Meeths et al. 2011. PubMed ID: 21931115
  • Nagafuji et al. 2007. PubMed ID: 17606450
  • Nichols et al. 1998. PubMed ID: 9811875
  • Online Gene Essentiality, ogee.medgenius.info
  • Qian et al. 2014. PubMed ID: 24470399
  • Ren et al. 2010. PubMed ID: 20435885
  • Rigaud et al. 2006. PubMed ID: 17080092
  • Yamamoto. 2004. PubMed ID: 15466010
  • Yin et al. 1999. PubMed ID: 10598819
  • Zur Stadt et al. 2006. PubMed ID: 16278825

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


Specimen Types

Specimen Requirements and Shipping Details

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ORDER OPTIONS

View Ordering Instructions

1) Select Test Method (Backbone)


1) Select Test Type


2) Select Additional Test Options

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

No Additional Test Options are available for this test.

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