Cataract 3, Multiple Types (CTRCT3) via the CRYBB2 Gene

Cataract 3 (CTRCT3) is common congenital, bilateral, symmetrical, progressive, polymorphic vision disorder that causes blindness in children (Litt et al. 1997). It consists of multiple types of cataracts that have been described as structural cataracts with punctate and cerulean (peripheral bluish and white opacification in concentric layers) opacities (Pauli et al. 2007). CTRCT3 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 1998). Intrafamilial variability in the size and density of the sutural opacity or in the number and position of the cerulean spots commonly occurs in CTRCT3 (Vanita et al. 2001; Lou et al. 2009; Weisschuh et al. 2012). The majority of individuals with CTRCT3 notice visual impairment before the age of 10 (Kramer et al. 1996; Li et al. 2008; Mothobi et al. 2009). 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 (Yao et al. 2005, 2011; 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). Some individuals with CTRCT3 may exhibit microphthalmia, microcornea, and strabismus (Kramer et al. 1996).

CTRCT3 is an autosomal dominant vision disorder that is caused by pathogenic sequence variants in the crystallin, beta-B2 (CRYBB2) gene, which is located on chromosome 22q11.23 (Kramer et al. 1996; Garnai et al. 2014). The CRYBB2 gene consists of five coding exons that encode a 205-amino acid structural protein called beta-crystallin B2, which is the most abundant and water-soluble beta-crystallin protein in the epithelial cells of the human lens (Gill et al. 2000). The CRYBB2 protein plays an important structural role in the maintenance of lens transparency and refractive index (Chen et al. 2013). Pathogenic sequence variants in the CRYBB2 gene significantly reduces the solubility and changes biophysical properties of the beta-crystallin B2, which are critical for lens transparency (Liu and Liang 2005; Chen et al. 2013). To date, a total of about 20 pathogenic CRYBB2 sequence variants have been reported, which are mostly missense and a few chain terminations (nonsense) and complex rearrangements (Human Gene Mutation Database). A recent study has indicated that the CRYBB2 protein is also expressed in the mammalian brain and may play a role in hippocampal function and behavioral phenotypes (Sun et al. 2013).

The clinical sensitivity of this test may range up to 10%. In three independent investigations performed in China, none (0/25; Sun et al. 2011), 5.6% (1/18; Sun et al. 2014), and 10% (2/20; Wang et al. 2011) of families with congenital cataracts harbored pathogenic sequence variants in the CRYBB2 gene. In two independent studies conducted in India, 1.7% (1/60; Devi et al. 2008), 2% (2/100; Kumar et al. 2013) of families with inherited pediatric cataract tested positive for disease-causing CRYBB2 sequence variants. In Denmark, 7% (2/28) of families with hereditary congenital cataract carried a pathogenic sequence variant in the CRYBB2 gene (Hansen et al. 2009).

This test provides full coverage of all coding exons of the CRYBB2 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).