Cataract 23 (CTRCT23) via the CRYBA4 Gene

Cataract 23 (CTRCT23) is a common congenital, bilateral, lamellar vision disorder that causes blindness in infants (Zhou et al. 2010). It is characterized by the development of blurred and dimmed vision resulting from clouding of the lens (opacification) due to changes in its microarchitecture (Kumar et al. 2013). This particular damage to the lens induces light to scatter as well as proteins to aggregate, thereby resulting in loss of transparency (Hejtmancik 2008). Intrafamilial variability in the morphology and location within the lens commonly occurs in CTRCT23 (Billingsley et al. 2006). The incidence of congenital cataract has been estimated to be roughly 2.5 per 10,000 live births (Wirth et al. 2002; Yi et al. 2011). Perinatal ocular examination in newborns via red reflex examination is generally conducted using an ophthalmoscope (American Academy of Pediatrics 2002), whereas young children are assessed by slit-lamp microscopy (Li et al. 2013). Congenital cataract is usually treated by surgery and early primary intraocular lens implantation during the first year of life (Ventura et al. 2013).

CTRCT23 is an autosomal dominant vision disorder that is caused by pathogenic sequence variants in the crystallin, beta-A4 (CRYBA4) gene, which is located on chromosome 22q12.1 (Billingsley et al. 2006). The CRYBA4 gene consists of five coding exons that encode a 196-amino acid structural protein called beta-crystallin A4, which plays an important role in the maintenance of lens transparency and refractive index. Pathogenic sequence variants in the CRYBA4 gene significantly reduces the stability of the beta-crystallin A4 monomer, thus disrupting protein folding. These disease-causing variants also interfere with interactions with other cyrstallin proteins (i.e., CRYBA3 and CRYBB3) that are critical for lens transparency. The CRYBA4 protein is 92%-94% similar to the rat and bovine beta-A4 crystallin proteins (Lampi et al. 1997). The developing human lens consists of approximately 11 major soluble proteins, of which 5% comprises the CRYBA4 protein. To date, a total of about 5 pathogenic CRYBA4 sequence variants have been reported, all of which are missense variants (Human Gene Mutation Database).

The clinical sensitivity of this test may range up to 8%. In three independent studies conducted in India, none of the 60 pediatric cataract cases (Devi et al. 2008), 3.1% (1/32) of patients with lamellar cataract and microphthalmia (Billingsley et al. 2006), and 8% (8/100) of congenital cataract cases (Kumar et al. 2013) showed causative CRYBA4 sequence variants.

This test provides full coverage of all coding exons of the CRYBA4 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).