Anterior Segment Dysgenesis Disorders Panel

Anterior segment dysgenesis disorders (ASDD) are rare developmental disorders in which the anterior segment of the eye including the iris, cornea, lens and trabecular meshwork are affected and result in a spectrum of anomalies such as aniridia, cataracts and glaucoma that lead to visual disability in childhood (Ito and Walter. 2014. PubMed ID: 24433355; Brémond-Gignac et al. 2010. PubMed ID: 20806047; Semina et al. 2001. PubMed ID: 11159941).

ASD can be an isolated or a syndromic disorder with systemic defects. Onset varies from congenital, juvenile and later depending on type of disorder (Reis and Semina. 2011. PubMed ID: 21730847). The most common syndromic ASD disorders are Axenfeld–Rieger syndrome (ARS), Peters’ anomaly, and the systemic anomalies Alagille syndrome, SHORT syndrome and Pierson syndrome (Doucette et al. 2011. PubMed ID: 21150893). ASD is associated with an ~50% risk for glaucoma (Alward. 2000. PubMed ID: 11004268). The incidence of glaucoma in ARS patients with pathogenic variants in PITX2 or FOXC1 has been reported to be 75%, rising to 100% in patients with pathogenic duplication in FOXC1 (Kelberman et al. 2011. PubMed ID: 21837767).

With the advent of gene therapy and other types of treatments, the identification of causative genes and variants is becoming increasingly important.

Anterior segment dysgenesis (ASD) demonstrates both autosomal dominant and recessive patterns of inheritance and often with incomplete penetrance/variable expressivity (Alward. 2000. PubMed ID: 11004268).

Pathogenic variants in genes encoding transcription factors such as PAX6, PITX2, FOXC1, FOXE3 and PITX3, which are expressed during the migration of neural crest cells in eye development, have been associated with ASDD such as aniridia, Axenfeld–Rieger syndrome and Peters anomaly (Doucette et al. 2011. PubMed ID: 21150893). Pathogenic variants in genes that encode structural components of the eye, such as the crystallins (CRYAA, CRYAB, CRYBA1, CRYBB1, CRYBB2, CRYBB3, CRYBA4, CRYGS, CRYGC, CRYGD), and lens-specific connexins (GJA3, GJA8) are associated with various forms of ASDD such as congenital cataracts and microcornea-cataract syndrome (Hejtmancik. 2008. PubMed ID: 18035564; Doucette et al. 2011. PubMed ID: 21150893). The remainder encode membrane proteins (aquaporin-0 AQP0, also known as MIP), cytoskeletal structural proteins (beaded filament structural proteins BFSP1 and BFSP2) and others (FYCO1, GCNT2, HSF4, LIM2, SIL1, TDRD7, FOXE3, CHMP4B, EPHA2, SLC33A1, AGK, FOXC1, MYOC, OPTN, or WDR36) (Hejtmancik. 2008. PubMed ID: 18035564).

De novo pathogenic variants have been reported in FOXC1 and PITX2 (Ito et al. 2007. PubMed ID: 17210863; Medina-Trillo et al. 2019. PubMed ID: 30657791; Pasutto et al. 2015. PubMed ID: 25967385).

A single digenic inheritance case has been reported in a family who segregated variants in both PITX2 (p.Ser233Leu) and FOXC1 (c.609delC). The most severely affected individual inherited both variants from affected parents. FOXC1 and PITX2 are capable of independently activating transcription of the target genes that are expressed during anterior segment development and the lowest transactivation activity is observed when both pathogenic variants are present together (Kelberman et al. 2011. PubMed ID: 21837767).

To gain insight into the diverse roles of PITX2 in vertebrate development and associated phenotypes, a zebrafish model was generated by introducing genetic variations in PITX2 via TALEN-mediated genome editing that resulted in complete knockout. Affected homozygous zebrafish exhibited congenital defects consistent with the range of PITX2-associated human phenotypes such as ocular and craniofacial defects. Also, this analysis identified the link between PITX2 and the WNT pathway and suggested a new role in regulation of corneal collagens gene expression during development (Hendee et al. 2018. PubMed ID: 29506241)

See individual gene test descriptions for more information on molecular biology of gene products and spectra of pathogenic variants.

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; D'haene et al. 2011. PubMed ID: 20881294; Thanikachalam et al. 2020. PubMed ID: 32224865).

Another study reported that 3.6% (9/251) of the patients with primary open-angle glaucoma had pathogenic variants in the CYP1B1, MYOC, and OPTN genes (Kumar et al. 2007. PubMed ID: 17563717).

Whole exome sequencing identified pathogenic variants in CRYAA, CRYBB1, CRYBB3, CRYGC, CRYGD, GJA8 and MIP in 9 probands from 23 pedigrees (39%) affected by familial dominant cataract (Reis et al. 2013. PubMed ID: 23508780). Screening in 25 Chinese families with congenital cataracts identified pathogenic variants in 10 families (40%) in 12 genes encoding crystallins (CRYAA, CRYAB, CRYBA1, CRYBB1, CRYBB2, CRYBB3, CRYBA4, CRYGS, CRYGC, CRYGD), and connexins (GJA3 and GJA8). Approximately 32% of the families had pathogenic variants in crystallin genes and 8% of the families had pathogenic variants in connexin genes (Sun et al. 2011. PubMed ID: 21866213).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 98.9% 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. 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).