Autoimmune Lymphoproliferative Syndrome via the FAS Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
1648 FAS$810.00 81479 Add to Order
Targeted Testing

For ordering targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 18 days.

Clinical Sensitivity

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).

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 FAS$690.00 81479 Add to Order
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Turnaround Time

The great majority of tests are completed within 28 days.

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).


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).

Testing Strategy

This test involves bidirectional Sanger sequencing using genomic DNA of all coding exons of the FAS gene plus ~20 bp of flanking non-coding DNA on each side. We will also sequence any single exon (Test #100) in family members of patients with a known mutation or to confirm research results.

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).


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


Name Inheritance OMIM ID
Autoimmune Lymphoproliferative Syndrome 601859


Genetic Counselors
  • 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.
  • 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
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Bi-Directional Sanger Sequencing

Test Procedure

Nomenclature for sequence variants was from the Human Genome Variation Society (  As required, DNA is extracted from the patient specimen.  PCR is used to amplify the indicated exons plus additional flanking non-coding sequence.  After cleaning of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  Products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In most cases, sequencing is performed in both forward and reverse directions; in some cases, sequencing is performed twice in either the forward or reverse directions.  In nearly all cases, the full coding region of each exon as well as 20 bases of non-coding DNA flanking the exon are sequenced.

Analytical Validity

As of March 2016, we compared 17.37 Mb of Sanger DNA sequence generated at PreventionGenetics to NextGen sequence generated in other labs. We detected only 4 errors in our Sanger sequences, and these were all due to allele dropout during PCR. For Proficiency Testing, both external and internal, in the 12 years of our lab operation we have Sanger sequenced roughly 8,800 PCR amplicons. Only one error has been identified, and this was due to sequence analysis error.

Our Sanger sequencing is capable of detecting virtually all nucleotide substitutions within the PCR amplicons. Similarly, we detect essentially all heterozygous or homozygous deletions within the amplicons. Homozygous deletions which overlap one or more PCR primer annealing sites are detectable as PCR failure. Heterozygous deletions which overlap one or more PCR primer annealing sites are usually not detected (see Analytical Limitations). All heterozygous insertions within the amplicons up to about 100 nucleotides in length appear to be detectable. Larger heterozygous insertions may not be detected. All homozygous insertions within the amplicons up to about 300 nucleotides in length appear to be detectable. Larger homozygous insertions may masquerade as homozygous deletions (PCR failure).

Analytical Limitations

In exons where our sequencing did not reveal any variation between the two alleles, we cannot be certain that we were able to PCR amplify both of the patient’s alleles. Occasionally, a patient may carry an allele which does not amplify, due for example to a deletion or a large insertion. In these cases, the report contains no information about the second allele.

Similarly, our sequencing tests have almost no power to detect duplications, triplications, etc. of the gene sequences.

In most cases, only the indicated exons and roughly 20 bp of flanking non-coding sequence on each side are analyzed. Test reports contain little or no information about other portions of the gene, including many regulatory regions.

In nearly all cases, we are unable to determine the phase of sequence variants. In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.

Our ability to detect minor sequence variants, due for example to somatic mosaicism is limited. Sequence variants that are present in less than 50% of the patient’s nucleated cells may not be detected.

Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during PCR and cycle sequencing.

Unless otherwise indicated, the sequence data that we report are based on DNA isolated from a specific tissue (usually leukocytes). Test reports contain no information about gene sequences in other tissues.

Deletion/Duplication Testing via Array Comparative Genomic Hybridization

Test Procedure

Equal amounts of genomic DNA from the patient and a gender matched reference sample are amplified and labeled with Cy3 and Cy5 dyes, respectively. To prevent any sample cross contamination, a unique sample tracking control is added into each patient sample. Each labeled patient product is then purified, quantified, and combined with the same amount of reference product. The combined sample is loaded onto the designed array and hybridized for at least 22-42 hours at 65°C. Arrays are then washed and scanned immediately with 2.5 µM resolution. Only data for the gene(s) of interest for each patient are extracted and analyzed.

Analytical Validity

PreventionGenetics' high density gene-centric custom designed aCGH enables the detection of relatively small deletions and duplications within a single exon of a given gene or deletions and duplications encompassing the entire gene. PreventionGenetics has established and verified this test's accuracy and precision.

Analytical Limitations

Our dense probe coverage may allow detection of deletions/duplications down to 100 bp; however due to limitations and probe spacing this cannot be guaranteed across all exons of all genes. Therefore, some copy number changes smaller than 100-300 bp within a targeted large exon may not be detected by our array.

This array may not detect deletions and duplications present at low levels of mosaicism or those present in genes that have pseudogene copies or repeats elsewhere in the genome.

aCGH will not detect balanced translocations, inversions, or point mutations that may be responsible for the clinical phenotype.

Breakpoints, if occurring outside the targeted gene, may be hard to define.

The sensitivity of this assay may be reduced when DNA is extracted by an outside laboratory.

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Ordering Options

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.
  • 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.


(Delivery accepted Monday - Saturday)

  • Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
  • For small babies, we require a minimum of 1 ml of blood.
  • Only one blood tube is required for multiple tests.
  • Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
  • During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
  • In cold weather, include an unfrozen ice pack in the shipping container as insulation.
  • At room temperature, blood specimen is stable for up to 48 hours.
  • If refrigerated, blood specimen is stable for up to one week.
  • Label the tube with the patient name, date of birth and/or ID number.


(Delivery accepted Monday - Saturday)

  • Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
  • For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
  • DNA may be shipped at room temperature.
  • Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
  • We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.


(Delivery preferred Monday - Thursday)

  • PreventionGenetics should be notified in advance of arrival of a cell culture.
  • Culture and send at least two T25 flasks of confluent cells.
  • Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
  • Send specimens in insulated, shatterproof container overnight.
  • Cell cultures may be shipped at room temperature or refrigerated.
  • Label the flasks with the patient name, date of birth, and/or ID number.
  • We strongly recommend maintaining a local back-up culture. We do not culture cells.
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