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Autoimmune Lymphoproliferative Syndrome via the FAS Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
8323 FAS 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
8323FAS81479 81479,81479 $890 Order Options and Pricing

Pricing Comments

Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information. If the Sanger option is selected, CNV detection may be ordered through Test #600.

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 backbone).

Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing backbone).

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

Turnaround Time

18 days on average for standard orders or 13 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.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • Megan Piazza, PhD, FACMG

Clinical Features and Genetics

Clinical Features

Autoimmune Lymphoproliferative Syndrome (ALPS) is a disorder characterized by dysregulation of lymphocyte hemostasis resulting in elevation of non-malignant lymphocyte numbers. Affected individuals present with lymphadenopathy, hepatomegaly, and splenomegaly during the first years of life. In the second decade of life, patients often experience autoimmune attacks on red blood cells (hemolytic anemia), neutrophils (neutropenia), or platelets (thrombocytopenia) due to production of autoantibodies. Other symptoms may include arthritis, vasculitis, oral ulcers, skin rash, and heightened risk for development of lymphoma (Bleesing et al. 2011). Homozygous affected patients display severe forms of the disease with lymphoproliferation leading to autoimmune disease and/or lymphoma early in life. ALPS is caused by mutations in either the FAS (~75%), FASLG (<5%), or CASP10 (<5%) gene. Patients with ALPS may be treated with immunosuppressive therapies such as corticosteroids to maintain lymphocyte homeostasis (Rao and Oliveira 2011). Genetic testing is helpful in differential diagnosis of ALPS from other immune disorders such as common variable immunodeficiency disease, Hyper IgM syndrome (Test #1653), X-linked lymphoproliferative disease, Wiskott-Aldrich syndrome (Test #440) and from other forms of ALPS (Bleesing et al. 2011).

Genetics

ALPS is inherited in an autosomal dominant manner through mutations in either the FAS, FASLG, or CASP10 gene. Mutations in the FAS gene primarily occur in the germline for individuals with ALPS (~70% of cases) but can also occur somatically in double negative (CD4-CD8-) α/β T cells (~15% of cases) leading to disease (Neven et al. 2011; Holzelova et al. 2004). Homozygous and compound heterozygous mutations in the FAS gene have been reported in ALPS patients with severe disease. Mutations in the FASLG or CASP10 gene each account for <5% of cases of ALPS. Mutations are found throughout the FAS gene with the majority occurring within exons 7-9 which encode the intracellular domains of Fas and lead to dominant negative functional effects (Fisher et al. 1995). Missense (40% cases), nonsense (15%), splice site (20%), and small insertion/deletions (18%) have all been reported to be causative for ALPS (NIAID ALPS Database). Penetrance for defective Fas-mediated apoptosis is 100%, but clinical penetrance is variable as relatives heterozygous for disease causing mutations have been reported to lack ALPS clinical symptoms (Jackson et al. 1999). The FAS gene encodes the Fas receptor which binds its ligand, FasL. This receptor ligand interaction is essential controlling lymphocyte populations by facilitating apoptosis to prevent autoimmune disease and non-malignant lymphoproliferation (Bleesing et al. 2011).

Clinical Sensitivity - Sequencing with CNV PGxome

Mutations in the FAS gene account for ~75% cases of ALPS. Detection of germ line mutations in the FAS gene in patients meeting strict ALPS criteria is 65-70% (Bleesing et al. 2011). Identification of somatically acquired FAS mutations is best performed on DNA extracted from flow cytometric sorted double negative (CD4-CD8-) α/β T cells, but may also be detected through sequencing analysis from a standard blood draw (Magerus-Chatinet et al. 2009). Analytical sensitivity is >99% as full gene deletions have not been reported in the FAS gene to date (NIAID ALPS Database).

Testing Strategy

This test provides full coverage of all coding exons of the FAS gene 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 full 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

Elevated double negative (CD4-CD8-) α/β T cells in blood, elevated plasma IL-10, and Coomb’s Test positive are indications for ALPS (Magrus-Chatinet et al. 2009). Defective lymphocyte apoptosis and elevated IgA, IgG, and IgM antibody levels are also indicative for ALPS. Strongest candidates have a family history for ALPS (Bleesing et al. 2011).

Gene

Official Gene Symbol OMIM ID
FAS 134637
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Autoimmune Lymphoproliferative Syndrome AD 601859

Related Test

Name
Autoimmune Lymphoproliferative Syndrome/ALPS Panel

Citations

  • Bleesing JJ, Johnson J, Zhang K. 2011. Autoimmune Lymphoproliferative Syndrome. In: Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews(®), Seattle (WA): University of Washington, Seattle. PubMed ID: 20301287
  • Fisher GH, Rosenberg FJ, Straus SE, Dale JK, Middleton LA, Lin AY, Strober W, Lenardo MJ, Puck JM. 1995. Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell 81: 935–946. PubMed ID: 7540117
  • Holzelova E, Vonarbourg C, Stolzenberg M-C, Arkwright PD, Selz F, Prieur A-M, Blanche S, Bartunkova J, Vilmer E, Fischer A, Deist F Le, Rieux-Laucat F. 2004. Autoimmune lymphoproliferative syndrome with somatic Fas mutations. N. Engl. J. Med. 351: 1409–1418. PubMed ID: 15459302
  • Jackson CE, Fischer RE, Hsu AP, Anderson SM, Choi Y, Wang J, Dale JK, Fleisher TA, Middelton LA, Sneller MC, others. 1999. Autoimmune lymphoproliferative syndrome with defective Fas: genotype influences penetrance. The American Journal of Human Genetics 64: 1002–1014. PubMed ID: 10090885
  • Magerus-Chatinet A, Stolzenberg M-C, Loffredo MS, Neven B, Schaffner C, Ducrot N, Arkwright PD, Bader-Meunier B, Barbot J, Blanche S, Casanova J-L, Debre M, et al. 2009. FAS-L, IL-10, and double-negative CD4-CD8- TCR / + T cells are reliable markers of autoimmune lymphoproliferative syndrome (ALPS) associated with FAS loss of function. Blood 113: 3027–3030. PubMed ID: 19176318
  • National Institute of Allergy and Infection Disease. ALPS Database. http://www.niaid.nih.gov/topics/alps/Pages/default.aspx
  • Neven B, Magerus-Chatinet A, Florkin B, Gobert D, Lambotte O, Somer L De, Lanzarotti N, Stolzenberg M-C, Bader-Meunier B, Aladjidi N, Chantrain C, Bertrand Y, et al. 2011. A survey of 90 patients with autoimmune lymphoproliferative syndrome related to TNFRSF6 mutation. Blood 118: 4798–4807. PubMed ID: 21885602
  • Rao VK, Oliveira JB. 2011. How I treat autoimmune lymphoproliferative syndrome. Blood 118: 5741–5751. PubMed ID: 21885601

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

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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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.
Total Price: $
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