Axenfeld-Rieger Syndrome Panel

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
10263 ASPH 81479,81479 Order Options and Pricing
B3GLCT 81479,81479
COL4A1 81408,81479
CYP1B1 81404,81479
FOXC1 81479,81479
FOXE3 81479,81479
PAX6 81479,81479
PITX2 81479,81479
SH3PXD2B 81479,81479
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
10263Genes x (9)81479 81404, 81408, 81479 $990 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

Axenfeld-Rieger syndrome (ARS) is a rare, highly penetrant 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. PubMed ID: 16274491; Berry et al. 2006. PubMed ID: 16449236; Waldron et al. 2010. PubMed ID: 20831741; Tümer and Bach-Holm. 2009. PubMed ID: 19513095; Chang et al. 2012. PubMed ID: 22199394). Dental abnormalities in this syndrome help in diagnosis and 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. PubMed ID: 16238657). The major clinical concern is high risk of developing open-angle glaucoma, which represents the main challenge in terms of treatment. Approximately 50% of ARS affected patients develop glaucoma (Shields et al. 1985. PubMed ID: 389274; Alward. 2000. PubMed ID: 11004268; Hjalt and Semina. 2005. PubMed ID: 16274491; Chang et al. 2012. PubMed ID: 22199394). ARS affected patients also need surveillance and management of sensorineural hearing loss, and cardiac, endocrinological, craniofacial and orthopaedic defects (Chang et al. 2012. PubMed ID: 22199394). Rieger syndrome (RIEG) and Peters anomaly both are in the anterior chamber cleavage group of anomalies and are considered to be variations of a single developmental disorder (the ARS group) (Reese and Ellsworth. 1966. PubMed ID: 5948260). RIEG is characterized by malformations of the eyes, teeth, and umbilicus; whereas Peters anomaly displays only ocular features (Amendt et al. 2000. PubMed ID: 11092457; Doward et al. 1999. PubMed ID: 10051017).

Genetics

Pathogenic variants in the FOXC1 or PITX2 genes cause autosomal dominant (AD) Axenfeld-Rieger syndrome (ARS). Linkage studies identified four chromosomal loci (4q25, 6p25, 13q14 and 16q24) that are associated with ARS and related or overlapping phenotypes. The genes that have been identified on chromosomes 4q25 and 6p25 are PITX2 (the pituitary homeobox 2 gene) and FOXC1 (the forkhead box C1 gene, also known as FKHL7) respectively (Alward. 2000. PubMed ID: 11004268; Lines et al. 2002. PubMed ID: 12015277; Tümer and Bach-Holm. 2009. PubMed ID: 19513095). PITX2 and FOXC1 are transcription factor genes which are expressed throughout eye ontogeny (Lines et al. 2002. PubMed ID: 12015277). The genes at 13q14 and 16q24 have not yet been discovered.

PITX2 encodes a Paired-like homeodomain transcription factor (PITX2), 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. PubMed ID: 18367164; Gage and Zacharias. 2009. PubMed ID: 19623614 ). The product of the FOXC1 gene (FOXC1) is reported to maintain homeostasis in trabecular meshwork (TM) cells by regulating genes that play an important role in stress response (Ito et al. 2014. PubMed ID: 24556684; Paylakhi et al. 2013. PubMed ID: 23541832). TM helps in regulating intraocular pressure by acting as a drainage structure for aqueous humor (Tamm. 2009. PubMed ID: 19239914). Pathogenic mutations in FOXC1 significantly decrease the TM cell viability and subsequently contribute to the development of glaucoma.

A Genotype-Phenotype correlation study indicated that patients with PITX2 pathogenic variants have a more severe prognosis for glaucoma as compared to FOXC1 pathogenic variants. Within FOXC1 pathogenic variants, patients with FOXC1 duplications are at higher risk for the development of glaucoma, which emphasizes the importance of genetic testing. It’s 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. PubMed ID: 16449236). Also, co-inheritance of PITX2 and FOXC1 pathogenic variants has been reported in a family which segregated with the disease and showed variable phenotypic expression. The most severely affected individual had pathogenic variants in both genes, whereas single heterozygous variants caused milder ARS phenotypes (Kelberman et al. 2011). So far, about 80 and 100 ARS causative variants have been identified in the PITX2 and FOXC1 genes, respectively (Human Gene Mutation Database).

Pathogenic variants in COL4A1 also cause AD ARS (Sibon et al. 2007. PubMed ID: 17696175). Pathogenic variants in SH3PXD2B cause autosomal recessive (AR) Frank-ter Haar syndrome. SH3PXD2B analysis in Axenfeld-Rieger syndrome patients identified several rare variants. However, the pathogenicity of these have not been well documented (Mao et al. 2012. PubMed ID: 22509100). Pathogenic variants in PAX6 and CYP1B1 have been shown to be associated with AD Peters anomaly (Hanson et al. 1994. PubMed ID: 8162071; Vincent et al. 2001. PubMed ID: 11403040). Pathogenic variants in ASPH cause AR Traboulsi syndrome or facial dysmorphism, lens dislocation, anterior-segment abnormalities, and spontaneous filtering blebs disorder (Patel et al. 2014. PubMed ID: 24768550). Pathogenic variants in FOXE3 cause AR anterior segment dysgenesis 2, multiple subtypes including Peters anomaly (Doucette et al. 2011. PubMed ID: 21150893). Pathogenic variants in B3GLCT cause AR Peters-plus syndrome (Lesnik Oberstein et al. 2006. PubMed ID: 16909395).

A wide variety of causative variants (missense, nonsense, splicing, small deletions and insertions) have been reported in Axenfeld-Rieger syndrome and overlapping phenotypes -associated genes including large deletions/duplications and complex genomic rearrangements in a few genes (FOXC1, PAX6, CYP1B1, B3GLCT and PITX2) (Human Gene Mutation Database).

See individual gene test descriptions for more information on molecular biology of gene products.

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. PubMed ID: 19513095; Reis et al. 2012. PubMed ID: 22569110; Alward. 2000. PubMed ID: 11004268). In one study, two out of 30 Axenfeld-Rieger syndrome patients (6.7%) carried SH3PXD2B sequence variants (Mao et al. 2012. PubMed ID: 2250910). Due to the phenotypic and genotypic heterogeneity, clinical sensitivity of the other genes in this panel is difficult to predict.

Large deletions/duplications or complex genomic rearrangements have been reported in FOXC1, PAX6, CYP1B1, B3GLCT and PITX2 (Human Gene Mutation Database).

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. A small region in exon 1 of FOXE3 is not covered for technical reasons.

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

All patients with symptoms suggestive of Axenfeld–Rieger syndrome, Rieger syndrome and Peters anomaly are candidates.

Genes

Official Gene Symbol OMIM ID
ASPH 600582
B3GLCT 610308
COL4A1 120130
CYP1B1 601771
FOXC1 601090
FOXE3 601094
PAX6 607108
PITX2 601542
SH3PXD2B 613293
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Test

Name
PGxome®

Citations

  • Alward. 2000. PubMed ID: 11004268
  • Amendt et al. 2000. PubMed ID: 11092457
  • Berry et al. 2006. PubMed ID: 16449236
  • Chang et al. 2012. PubMed ID: 22199394
  • Doucette et al. 2011. PubMed ID: 21150893
  • Doward et al. 1999. PubMed ID: 10051017
  • Gage and Zacharias. 2009. PubMed ID: 19623614
  • Gage et al. 2008. PubMed ID: 18367164
  • Hanson et al. 1994. PubMed ID: 8162071
  • Hjalt and Semina. 2005. PubMed ID: 16274491
  • Huang et al. 2009. PubMed ID: 19174163
  • Human Gene Mutation Database (Bio-base).
  • Ito et al. 2014. PubMed ID: 24556684
  • Kelberman et al. 2011. PubMed ID: 21837767
  • Lesnik Oberstein et al. 2006. PubMed ID: 16909395
  • Lines et al. 2002. PubMed ID: 12015277
  • Mao et al. 2012. PubMed ID: 22509100
  • O'Dwyer and Jones. 2005. PubMed ID: 16238657
  • Patel et al. 2014. PubMed ID: 24768550
  • Paylakhi et al. 2013. PubMed ID: 23541832
  • Reese and Ellsworth. 1966. PubMed ID: 5948260
  • Reis et al. 2012. PubMed ID: 22569110
  • Shields et al. 1985. PubMed ID: 3892740
  • Sibon et al. 2007. PubMed ID: 17696175
  • Tamm. 2009. PubMed ID: 19239914
  • Tümer and Bach-Holm. 2009. PubMed ID: 19513095
  • Vincent et al. 2001. PubMed ID: 11403040
  • Waldron et al. 2010. PubMed ID: 20831741

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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ORDER OPTIONS

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2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

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