Autoimmune Lymphoproliferative Syndrome/ALPS Panel

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
4921 CASP10 81479,81479 Order Options and Pricing
CASP8 81479,81479
CTLA4 81479,81479
FADD 81479,81479
FAS 81479,81479
FASLG 81479,81479
ITK 81479,81479
KRAS 81405,81479
LRBA 81479,81479
MAGT1 81479,81479
NRAS 81479,81479
PIK3CD 81479,81479
PRKCD 81479,81479
SH2D1A 81404,81403
STAT3 81479,81479
XIAP 81479,81479
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
4921Genes x (16)81479 81403, 81404, 81405, 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

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 primarily in 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., 2017. PubMed ID: 20301287). Adult forms of ALPS have recently been described with some individuals developing life threatening end organ lymphoproliferative disease (Niemela et al., 2011. PubMed ID: 21079152). Patients with ALPS may be treated with immunosuppressive therapies such as corticosteroids to maintain lymphocyte homeostasis (Rao and Oliveira, 2011. PubMed ID: 21885601). There are 5 different subtypes of ALPS distinguished by their underlying genetic cause: type 1A (FAS), type2B (FASLG), type 2A (CASP10), type 2B (CASP8), type 3 (PRKCD), type 4 (NRAS, KRAS), and type 5 (CTLA4). Genetic testing is helpful in identifying the subtype of ALPS as well as in differential diagnosis from other immune disorders. Other related disorders include common variable immunodeficiency disease (CVID), Hyper IgM syndrome, X-linked lymphoproliferative diseases, Wiskott-Aldrich syndrome and FADD deficiency, autoimmune disease multisystem infantile onset type 1/ADMIO1, and activated PI3K-δ syndrome type 1/APDS1 (Bleesing et al., 2017. PubMed ID: 20301287; Sumegi et al., 2000. PubMed ID: 11049992; Li et al., 2014. PubMed ID: 24550228; Linka et al., 2012. PubMed ID: 22289921; Stepensky et al., 2011. PubMed ID: 21109689; Bolze et al., 2010. PubMed ID: 21109225; Chun et al., 2002. PubMed ID: 12353035).

Genetics

ALPS is inherited in an autosomal dominant manner through pathogenic variants in either the FAS, FASLG, or CASP10 genes. Pathogenic variants 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-) a/b T cells (~15% of cases) leading to disease (Neven et al., 2011. PubMed ID: 21885602; Holzelova et al., 2004. PubMed ID: 15459302). Homozygous and compound heterozygous pathogenic variants in the FAS gene have been reported for ALPS with patients having severe disease. Pathogenic variants in the CASP10 or FASLG gene account for <5% and <1% of cases of ALPS respectively (Bleesing et al., 2017. PubMed ID: 20301287). A germline NRAS or somatic KRAS gain of function variant, designated p.Gly13Asp, has been reported in rare cases of ALPS (Oliveira et al., 2007. PubMed ID: 17517660; Niemela et al., 2011. PubMed ID: 21079152; Takagi et al., 2011. PubMed ID: 21063026). Gain of function pathogenic variants within the STAT3 and PIK3CD genes are responsible for ADMIO1 and APDS2 respectively, whereas loss of function pathogenic variants result in immunodeficiency syndromes (Angulo et al., 2013. PubMed ID: 24136356; Lucas et al., 2013. PubMed ID: 24165795; Haapaniemi et al., 2015. PubMed ID: 25349174). Disorders and inheritance patterns of other lymphoproliferative disorders are listed below.

Disorder

Gene

Inheritance

ALPS type 1A

FAS

AD, somatic

ALPS type 1B

FASLG

AD

ALPS type 2A

CASP10

AD

ALPS type 2B

CASP8

AR

ALPS type 3

PRKCD

AR

ALPS type 4

NRAS, KRAS

AD, somatic

ALPS type 5

CTLA4

AD

XLP type 1

SH2D1A

XR

XLP type 2

XIAP

XR

XMEN

MAGT1

XR

LPFS1

ITK

AR

FADD Deficiency

FADD

AR

APDS2

PIK3CD

AD

ADMIO1

STAT3

AD

CVID8

LRBA

AR

Apoptosis is an important process for maintaining lymphocyte homeostasis allowing responses to pathogens but avoiding autoimmune effects. Many of the genes involved in this panel facilitate apoptosis through a Fas-associated mechanism resulting in a cascade of caspase activation.

Clinical Sensitivity - Sequencing with CNV PGxome

Germline pathogenic variants in the FAS, FASLG and CASP10 genes account for about 75%, <5% and <5% of Autoimmune Lymphoproliferative Syndrome (ALPS) cases respectively. Somatic FAS variants account for about 15-20% of cases. Currently about 20% of cases of ALPS have an undefined genetic cause (Shah et al., 2014. PubMed ID: 25086580; Bleesing et al., 2017. PubMed ID: 20301287). Clinical sensitivity for the CASP8, FADD, ITK, KRAS, MAGT1, and NRAS genes for ALPS is currently unknown due to limited number of cases reported to date. Around 60% of X-linked Lymphoproliferative syndrome cases are attributed to pathogenic variants in the SH2D1A gene. Large deletions account for approximately 25% of all reported SH2D1A pathogenic variants (Arico et al., 2001. PubMed ID: 11159547).

Gross deletions in the FAS gene have only been reported in a few cases (Magerus-Chatinet et al., 2011. PubMed ID: 21183795; Pensati et al., 1997. PubMed ID: 9322534; van der Werff ten Bosch et al., 1998. PubMed ID: 9695976). Gain of function pathogenic variants in the STAT3, KRAS and NRAS genes have been reported to be causative for ALPS, and deletion/duplication testing has minimal clinical utility. Large deletions account for approximately 25% of all reported SH2D1A pathogenic variants (Arico et al., 2001. PubMed ID: 11159547). Large deletions in XIAP have been reported in Familial Hemophagocytic Lymphohistiocytosis patients, but make up < 10% of all reported XIAP pathogenic variants (Marsh et al., 2009. PubMed ID: 19398375).

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. Only exons 5, 10, 11, 14 and 21-23 will be analyzed for the STAT3 as only gain of function variants in these regions have been reported for patients with ADMIO1.

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

Diagnostic criteria for ALPS includes chronic, non-malignant, non-infectious lymphadenopathy, and elevated double negative CD3+ (CD4-CD8-) α/β T cells (>1.5% of total lymphocytes or 2.5% of CD3+ lymphocytes) in the setting of normal lymphocyte counts (Li et al., 2014. PubMed ID: 24550228). Elevated plasma IL-10, positive Coomb’s Test, defective lymphocyte apoptosis, elevated IgA, IgG, and IgM antibody levels are also indicative for ALPS. Complete diagnostic guidelines for ALPS were revised in 2009 (Oliveira et al., 2010. PubMed ID: 20538792). The strongest candidates have a family history for ALPS (Bleesing et al., 2017. PubMed ID: 20301287).

Genes

Official Gene Symbol OMIM ID
CASP10 601762
CASP8 601763
CTLA4 123890
FADD 602457
FAS 134637
FASLG 134638
ITK 186973
KRAS 190070
LRBA 606453
MAGT1 300715
NRAS 164790
PIK3CD 602839
PRKCD 176977
SH2D1A 300490
STAT3 102582
XIAP 300079
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Test

Name
PGxome®

Citations

  • Angulo et al., 2013. PubMed ID: 24136356
  • Arico et al., 2001. PubMed ID: 11159547
  • Bleesing et al., 2017. PubMed ID: 20301287
  • Bolze et al., 2010. PubMed ID: 21109225
  • Chun et al., 2002. PubMed ID: 12353035
  • Haapaniemi et al., 2015. PubMed ID: 25349174
  • Holzelova et. al., 2004. PubMed ID: 15459302
  • Li et al., 2014. PubMed ID: 24550228
  • Linka et al., 2012. PubMed ID: 22289921
  • Lucas et al., 2013. PubMed ID: 24165795
  • Magerus-Chatinet et al., 2011. PubMed ID: 21183795
  • Marsh et al., 2009. PubMed ID: 19398375
  • Neven et. al., 2011. PubMed ID: 21885602
  • Niemela et al., 2011. PubMed ID: 21079152
  • Oliveira et al., 2007. PubMed ID: 17517660
  • Oliveira et al., 2010. PubMed ID: 20538792
  • Pensati et al., 1997. PubMed ID: 9322534
  • Rao and Oliveira, 2011. PubMed ID: 21885601
  • Shah et al., 2014. PubMed ID: 25086580
  • Stepensky et al., 2011. PubMed ID: 21109689
  • Sumegi et al., 2000. PubMed ID: 11049992
  • Takagi et al., 2011. PubMed ID: 21063026
  • van der Werff ten Bosch et al., 1998. PubMed ID: 9695976

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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