PITX2- Related Disorders via the PITX2 Gene

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).

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).

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).