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Immunodysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) Syndrome via the FOXP3 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
8241 FOXP3 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
8241FOXP381479 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

IPEX syndrome is a disorder characterized by the loss of CD4+CD25+ regulatory T-cells which maintain immune homeostasis and provide protection against autoimmunity. Diagnosis of IPEX involves a triad presentation of autoimmune enteropathy, endocrinopathy, and dermatitis with disease onset occurring within the first few months of life. Gastrointestinal features include chronic diarrhea that worsens with underlying food allergies or infection (Torgerson et al. 2007). Small bowel is primarily affected with loss of crypt-villus architecture, ulcerations, and hyperemic mucosa. Neonatal type 1 diabetes and thyroiditis, typically hypothyroidism with elevated antithyroid antibodies, are the most common endocrinopathy manifestations. Atypical growth hormone deficiency and hypoadrenalism have also been reported in patients with IPEX. Dermatitis ranges from mild to severe eczema with severity being correlated to elevated serum IgE and eosinophilia (Hannibal and Torgerson 2011; Gambineri et al. 2008; Wildin et al. 2002). Treatment may include immune suppressive therapies and dietary modifications. Hematopoietic stem cell transplant is the only curative option. Other IPEX findings may include cytopenias, increased susceptibility to infections, renal disease, acute respiratory distress syndrome, and failure to thrive. Genetic testing is helpful in confirmation of IPEX diagnosis and for differential diagnosis from IPEX-like syndromes, eosinophilic enteropathies, and neonatal onset multisystemic inflammatory disease/NOMID (Verbsky and Chatila 2013).

Genetics

IPEX syndrome is inherited in an X-linked recessive manner through pathogenic variants of the FOXP3 gene. Causative variants in the FOXP3 gene are fully penetrant with truncating mutations such as nonsense, splice site, or frameshift changes occurring in about half of cases. Missense mutations leading to loss of FOXP3 function are also commonly reported. Currently there is no clear genotype/phenotype correlation. Most mutations are familial with sporadic cases being rare. Pathogenic variants occur throughout the coding region, the 5’ untranslated region, and at the poly adenylation site (Hannibal and Torgerson 2011; Gambineri er al. 2008; Owen et al. 2003). No affected females have been reported and carriers are unaffected. A gross deletion in the FOXP3 gene has only been reported in one case (Torgerson et al. 2007). The FOXP3 gene encodes the forkhead box protein P3 transcription factor which is involved in the development and function of regulatory T-cells. Regulatory T-cells play a fundamental role in immune homeostasis including modulation of autoimmune, allergic inflammation, and tolerance (Bacchetta et al. 2006; Chatila et al. 2000).

Clinical Sensitivity - Sequencing with CNV PGxome

In a group of 14 patients with suspected IPEX syndrome based on clinical features and immunological evaluation, 13 patients were found to have pathogenic variants in the FOXP3 gene (Wildin et al. 2002). Analytical sensitivity is >95% as gross deletions in the FOXP3 gene have only been reported in one case (Torgerson et al. 2007).

Testing Strategy

This test provides full coverage of all coding exons of the FOXP3 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).

This test also provides coverage of the first polyadenylation sites (c.*876 and c.*878).

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

Ideal candidates for testing present with the triad of clinical features including enteropathy, endocrinopathy, and dermatitis. Laboratory findings indicating immune dysregulation and suggestive of IPEX are elevated serum IgE and IgA, eosinophilia, autoimmune anemia, thrombocytopenia, neutropenia, autoantibodies to pancreatic islet or thyroid antigens, and a decrease in circulating CD4+FOXP3+ lymphocytes. Serum IgG and IgM, Coombs positive anemia, leukocyte counts, neutrophil function, and serum complement levels are usually normal within patients presenting with IPEX (Hannibal and Torgerson 2011).

Gene

Official Gene Symbol OMIM ID
FOXP3 300292
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Citations

  • Bacchetta R. 2006. Defective regulatory and effector T cell functions in patients with FOXP3 mutations. Journal of Clinical Investigation 116: 1713–1722. PubMed ID: 16741580
  • Chatila TA, Blaeser F, Ho N, Lederman HM, Voulgaropoulos C, Helms C, Bowcock AM. 2000. JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome. J. Clin. Invest. 106: R75-81. PubMed ID: 11120765
  • Gambineri E, Perroni L, Passerini L, Bianchi L, Doglioni C, Meschi F, Bonfanti R, Sznajer Y, Tommasini A, Lawitschka A, Junker A, Dunstheimer D, Heidemann PH, Cazzola G, Cipolli M, Friedrich W, Janic D, Azzi N, Richmond E, Vignola S, Barabino A, Chiumello G, Azzari C, Roncarolo MG, Bacchetta R. 2008. Clinical and molecular profile of a new series of patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome: Inconsistent correlation between forkhead box protein 3 expression and disease severity. Journal of Allergy and Clinical Immunology 122: 1105–1112.e1. PubMed ID: 18951619
  • Hannibal MC, Torgerson T. 2011. IPEX 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: 20301297
  • Owen CJ, Jennings CE, Imrie H, Lachaux A, Bridges NA, Cheetham TD, Pearce SHS. 2003. Mutational Analysis of the FOXP3 Gene and Evidence for Genetic Heterogeneity in the Immunodysregulation, Polyendocrinopathy, Enteropathy Syndrome. The Journal of Clinical Endocrinology & Metabolism 88: 6034–6039. PubMed ID: 14671208
  • Torgerson TR, Linane A, Moes N, Anover S, Mateo V, Rieux–Laucat F, Hermine O, Vijay S, Gambineri E, Cerf–Bensussan N, Fischer A, Ochs HD, Goulet O, Ruemmele FM. 2007. Severe Food Allergy as a Variant of IPEX Syndrome Caused by a Deletion in a Noncoding Region of the FOXP3 Gene. Gastroenterology 132: 1705–1717. PubMed ID: 17484868
  • Verbsky JW, Chatila TA. 2013. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) and IPEX-related disorders: an evolving web of heritable autoimmune diseases. Current Opinion in Pediatrics 25: 708–714. PubMed ID: 24240290
  • Wildin RS, Smyk-Pearson S, Filipovich AH. 2002. Clinical and molecular features of the immunodysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome. Journal of medical genetics 39: 537–545. PubMed ID: 12161590

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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