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PITX2- Related Disorders via the PITX2 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
PITX2 81479 81479,81479 $990
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
8917PITX281479 81479,81479 $990 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 platform).

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

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

For Sanger Sequencing click here.

Turnaround Time

3 weeks on average for standard orders or 2 weeks 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.


Genetic Counselors


  • Jamie Fox, PhD

Clinical Features and Genetics

Clinical Features

Axenfeld-Rieger syndrome (ARS) is a rare, highly penetrant autosomal dominant disorder characterized by varying degrees of eye anterior segment anomalies with systemic malformations such as dental hypoplasia and a protuberant umbilicus (Hjalt and Semina 2005; Berry et al. 2006; Waldron et al. 2010; Tümer and Bach-Holm 2009; Chang et al. 2012). Dental abnormalities in this syndrome helps in the diagnosis and also to distinguish ARS from other eye anterior segment abnormalities. Early diagnosis of ARS from its dento-facial and systemic features is essential in treating or preventing the most serious consequence of ARS (O’Dwyer and Jones 2005). The major clinical concern is high risk of developing open-angle glaucoma. Approximately 50% of the ARS affected patients develop glaucoma (Shields et al. 1985; Alward 2000; Hjalt and Semina 2005; Chang et al. 2012). ARS affected patients also need surveillance and management of sensorineural hearing loss, and cardiac, endocrinological, craniofacial and orthopaedic defects (Chang et al. 2012). Rieger syndrome (RIEG) and Axenfeld anomaly are both anterior chamber cleavage anomalies and considered to be variations of a single developmental disorder and belong to the ARS group (Reese and Ellsworth 1966). RIEG is characterized by malformations of the eyes, teeth, and umbilicus; whereas, Axenfeld anomaly displays only ocular features (Amendt et al. 2000).


Axenfeld-Rieger syndrome (ARS) is an autosomal dominant disorder caused by mutation in the PITX2 gene. Linkage studies mapped four chromosomal loci (4q25, 6p25, 13q14 and 16q24) that are involved with ARS and related or overlapping phenotypes. The genes that have been identified on chromosomes 4q25 and 6p25, PITX2 (the pituitary homeobox 2 gene) and FOXC1 (the forkhead box C1 gene, also known as FKHL7), respectively (Alward 2000; Lines et al. 2002; Tümer and Bach-Holm 2009), are known to be associated with ARS pathogenesis (Tümer and Bach-Holm 2009). PITX2 and FOXC1 are two transcription factor genes, which are expressed throughout eye ontogeny (Lines et al. 2002). PITX2 encodes a Paired-like homeodomain transcription factor, which plays a critical role in cell proliferation, differentiation, hematopoiesis and organogenesis (Huang et al. 2009). Also, PITX2 integrates retinoic acid and canonical Wnt signaling during eye anterior segment development (Gage et al. 2008; Gage and Zacharias 2009). Genotype-Phenotype correlation studies indicated that patients with PITX2 mutations have a more severe prognosis for glaucoma development as compared to FOXC1 mutations. Patients with FOXC1 duplications are at high risk for the development of glaucoma, which emphasizes the importance of genetic testing. Also, glaucoma in patients with PITX2 mutations is reported to be more difficult to treat than that in patients with FOXC1 mutations (Strungaru et al. 2007). It has been reported that PITX2 and FOXC1 interact with each other, which is essential for the regulation of common downstream target genes within specific cell lineages (Berry et al. 2006). Also, co-inheritance of PITX2 and FOXC1 mutations has been reported in a family, which segregated with the disease and showed variable phenotypic expression. The most severely affected individual had mutations in both genes, whereas the single heterozygous mutations caused mild ARS phenotypes (Kelberman et al. 2011). So far, about 80 mutations have been identified in PITX2 that are involved with ARS and related or overlapping phenotypes (Human Gene Mutation Database).

Clinical Sensitivity - Sequencing with CNV PGxome

Approximately 25%-60% of Axenfeld-Rieger syndrome cases are due to FOXC1 or PITX2 pathogenic variants (Tümer and Bach-Holm 2009; Reis et al. 2012; Alward 2000). In approximately half of ARS affected patients the genetic cause is unknown, which indicates that there are still more genes to be identified (Tümer and Bach-Holm 2009). Several gross deletions, duplications and complex rearrangements have been reported in PITX2 that are associated with ARS and related or overlapping phenotypes (Human Gene Mutation Database).

Testing Strategy

This test provides full coverage of all coding exons of the PITX2 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

All patients with symptoms suggestive of Axenfeld-Rieger syndrome and related phenotypes are candidates.


Official Gene Symbol OMIM ID
PITX2 601542
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


  • Alward WL. 2000. American Journal of Ophthalmology. 130: 107-15. PubMed ID: 11004268
  • Amendt BA. et al. 2000. Cellular and Molecular Life Sciences : Cmls. 57: 1652-66. PubMed ID: 11092457
  • Berry FB. et al. 2006. Human Molecular Genetics. 15: 905-19. PubMed ID: 16449236
  • Chang TC. et al. 2012. The British Journal of Ophthalmology. 96: 318-22. PubMed ID: 22199394
  • Gage PJ. et al. 2008. Developmental Biology. 317: 310-24. PubMed ID: 18367164
  • Gage PJ., Zacharias AL. 2009. Developmental Dynamics : an Official Publication of the American Association of Anatomists. 238: 2149-62. PubMed ID: 19623614
  • Hjalt TA., Semina EV. 2005. Expert Reviews in Molecular Medicine. 7: 1-17. PubMed ID: 16274491
  • Huang Y. et al. 2009. Febs Letters. 583: 638-42. PubMed ID: 19174163
  • Human Gene Mutation Database (Bio-base).
  • Kelberman D. et al. 2011. Human Mutatation. 32: 1144–52. PubMed ID: 21837767
  • Lines MA. et al. 2002. Human Molecular Genetics. 11: 1177–84. PubMed ID: 12015277
  • O'Dwyer E.M., Jones D.C. 2005. International Journal of Paediatric Dentistry. 15: 459-63. PubMed ID: 16238657
  • Reese AB., Ellsworth RM. 1966. Archives of Ophthalmology. 75: 307-18. PubMed ID: 5948260
  • Reis LM, Tyler RC, Volkmann Kloss BA, Schilter KF, Levin AV, Lowry RB, Zwijnenburg PJG, Stroh E, Broeckel U, Murray JC, Semina EV. 2012. PITX2 and FOXC1 spectrum of mutations in ocular syndromes. Eur. J. Hum. Genet. 20: 1224–1233. PubMed ID: 22569110
  • Shields MB. et al. 1985. Survey of Ophthalmology. 29: 387-409. PubMed ID: 3892740
  • Strungaru MH. et al. 2007. Investigative Ophthalmology & Visual Science. 48: 228-37. PubMed ID: 17197537
  • Tümer Z, Bach-Holm D. 2009. European Journal of Human Genetics : Ejhg. 17: 1527-39. PubMed ID: 19513095
  • Waldron JM. et al. 2010. Special Care in Dentistry : Official Publication of the American Association of Hospital Dentists, the Academy of Dentistry For the Handicapped, and the American Society For Geriatric Dentistry. 30: 218-22. PubMed ID: 20831741


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

If ordering a Duo or Trio test, the proband and all comparator samples are required to initiate testing. If we do not receive all required samples for the test ordered within 21 days, we will convert the order to the most effective testing strategy with the samples available. Prior authorization and/or billing in place may be impacted by a change in test code.

Specimen Types

Specimen Requirements and Shipping Details

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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2) Select Additional Test Options

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