Cataract Type 14 via the GJA3 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).

GJA3-associated cataracts are characterized as zonular pulverulent, posterior polar, nuclear coralliform, embryonal nuclear, and Coppock-like catatracts (Rees et al. 2000; Zhang et al. 2012).

Currently, isolated or primary cataracts have been mapped to about 40 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 GJA3 that encodes gap junction protein alpha-3 (also known as connexin-46-CX46) are shown to be causative for autosomal dominant cataracts with incomplete penetrance (Rees et al. 2000; Zhang et al. 2012). GJA3 encoded protein is first expressed when epithelial cells differentiate into lens fibers and is critical to lens transparency (Wang et al. 2017). Mostly missense variants have been documented causative, although rarely small frameshift deletions and one splicing variant have been documented causative (Human Gene Mutation Database).

Predicting clinical sensitivity for the GJA3 gene is challenging due to the genetic heterogeneity. However, all the reported causative variants are detectable by sequencing (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the GJA3 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).