Cataract 10, Multiple Types (CTRCT10) via the CRYBA1 Gene

Cataract 10, multiple types (CTRCT10) is a common, congenital, progressive, bilateral, symmetric, zonular, sutural vision disorder that causes blindness in infants (Hejtmancik 2008). 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; Kumar et al. 2013). Fibers internal and external to the zonular cataract remain clear, and the position and thickness of the opaque layer varies from person to person, ranging from dense to dotted or dusty appearance (Padma et al. 1995). 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).

CTRCT10 is an autosomal dominant vision disorder that is caused by pathogenic sequence variants in the crystallin, beta-A1 (CRYBA1) gene [also known as the crystallin, beta-1 (CRYB1) gene], which is located on chromosome 17q11.2 (Padma et al. 1995). The CRYBA1 gene consists of six coding exons, spanning approximately 8 kb, and encodes two proteins, namely, beta-A3- and beta-A1-crystallin. The production of two beta-crystallin proteins from a single CRYBA1 gene is attributable to the two potential initiation codons that are located in the first and second exons, with the shorter beta-A1 polypeptide differing by 17 amino acid residues at its N-terminus (Hogg et al. 1986; Werten et al. 1996; Lampi et al. 1997). Different beta-crystallin proteins are essential in the embryonic development of the lens and retina; these interact with each other and form oligomers of variable size (range: 2-8 units), as well as with other lens proteins to create a structural lattice. These protein-protein interactions also play a key role in maintaining lens transparency. To date, a total of about 8 pathogenic CRYBA1 sequence variants have been reported. These variants are mostly chain termination (splicing, deletion, frameshift) and a few missense variants (Human Gene Mutation Database). In vitro studies have suggested that these chain termination variants impair protein folding and solubility of beta-crystallin proteins (Reddy et al. 2004; Sinha et al. 2012).

The clinical sensitivity of this test may range up to 8%. In India, none of the 100 congenital cataract cases showed causative CRYBA1 sequence variants (Kumar et al. 2013). In Australia, 2.6% (1/38) of families with congenital cataract tested positive for disease-causing CRYBA1 sequence variants (Burdon et al. 2004). In China, 8% (2/25) of families with congenital cataracts harbored pathogenic sequence variants in the CRYBA1 gene (Sun et al. 2011).

This test provides full coverage of all coding exons of the CRYBA1 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).