Cataract Type 11 via the PITX3 Gene

Cataracts are described as opacification of the crystalline lens of the eye that result in abnormal refraction index and light scattering. Congenital cataracts (CC) are a serious and leading cause of reversible blindness in childhood. They account for about one-tenth of the cases of childhood blindness (Francis and Moore 2004). Estimated prevalence rate is 1.2 - 6.0 per 10,000 live births. Early diagnosis and surgery and optical correction have resulted in an improved outcome for infants with either unilateral or bilateral cataracts (Lambert and Drack 1996).

PITX3- associated posterior polar type is a clinically distinct opacity and appears as 2- to 3-mm disks of dense whitish material in the center of the posterior lens capsule (Bidinost et al. 2006; Berry et al. 2004).

Currently, isolated or primary cataracts have been mapped to about 39 genetic loci, and over 25 of those are connected to pathogenic variants in specific genes. However, this number is constantly increasing. Among the candidate genes, the majority of the identified pathogenic variants (about half) are in crystallins (CRYAA, CRYAB, CRYBA1, CRYBB1, CRYBB2, CRYBB3, CRYBA4, CRYGS, CRYGC, CRYGD), followed by (about a quarter) lens-specific connexins (GJA3, GJA8). The remainder are divided among growth and Transcription Factors (HSF4, MAF, PITX3), 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) (Hejtmancik 2008).

Heterozygous pathogenic variants in PITX3 are shown to be causative for autosomal dominant posterior polar cataract and variable anterior segment mesenchymal dysgenesis (Bidinost et al. 2006; Berry et al. 2004). Two siblings from a consanguineous marriage with a causative variant in the homozygous state showed a severe phenotype (Bidinost et al. 2006). Missense, small deletions and insertions have been shown to be causative (Human Gene Mutation Database). PITX3 encodes a homeobox bicoidlike transcription factor and plays an important role in lens and anterior segment development (Bidinost et al. 2006; Addison et al. 2005).

Predicting clinical sensitivity for the PITX3 gene is challenging due to the limited number of cases. However, all the reported causative variants are detectable by this method. Gross deletions or duplications have not been reported in this gene that are associated with cataracts. However, a deletion involving PITX3, along with 7 other genes, has been reported in Smith-Magenis-like syndrome (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the PITX3 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).