Comprehensive Cataracts Panel

Cataracts are defined 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 one-tenth of the cases of childhood blindness (Francis and Moore. 2004. PubMed ID: 14743013). Estimated prevalence rate is 1.2 - 6.0 per 10,000 live births. Early diagnosis, surgery and optical correction have resulted in an improved outcome for infants with either unilateral or bilateral cataracts (Lambert and Drack. 1996. PubMed ID: 8724637).

Only 10–25% of CC are hereditary. Cataracts are most often inherited as an autosomal dominant trait. CC also exhibit autosomal recessive or X-linked inheritance (Hejtmancik. 2008. PubMed ID: 18035564). X-linked cataract is seen in Nance-Horan syndrome (NHS), which is an especially rare disorder. NHS has cataract along with prominent dental findings, dysmorphic features, and intellectual disability (Toutain et al. 1997. PubMed ID: 9048931; Stambolian et al. 1990. PubMed ID: 1971992). Metabolic and some neurological disorders are also associated with CC (Cassidy and Taylor. 1999. PubMed ID: 10627826).

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, about half of the identified pathogenic variants are in crystallins (CRYAA, CRYAB, CRYBA1, CRYBB1, CRYBB2, CRYBB3, CRYBA4, CRYGS, CRYGC, CRYGD), followed by about a quarter in lens-specific connexins (GJA3, GJA8). The remainder are divided among growth and transcription factors (HSF4, MAF, PITX3), membrane protein 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. PubMed ID: 18035564).

The common genes associated with autosomal dominant inheritance include CRYAB, CRYBB2, CRYBA4, CRYGS, CRYGC, FOXE3, PITX3, CHMP4B, GJA3, MIP, EPHA2, BFSP2, SLC33A1, MAF, CRYBA1 (also known as CRYBA3), GJA8, CRYAA, HSF4, CRYGB, EYA1, MIR184, PAX6, SLC16A12, VIM and CRYGD. Common genes associated with autosomal recessive inheritance AGK, CRYBB3, FYCO1, GCNT2, LIM2, SIL1, TDRD7, BFSP1, PXDN,CTDP1, HYCC1/FAM126A, GALK1, P3H2 and CRYBB1. Pathogenic variants in NHS cause X-linked disorders. However, inheritance of the same variant in different families or within the same family can result in a varied clinical presentation of cataracts, which suggests the involvement of additional genes or modifying factors. On the other hand, identical clinical presentation of cataract is also possible due to variants in completely different genes (Hejtmancik. 2008. PubMed ID: 18035564; Santana and Waiswo. 2011. PubMed ID: 21779674; Chen et al. 2011. PubMed ID: 21636066; Pras et al. 2004. PubMed ID: 15161861; Haghighi et al. 2014. PubMed ID: 25208612).

Of note, we also offer focused test for cataracts that targets genes that are a relatively common cause of CC. See individual gene test descriptions for information on molecular biology of gene products and spectra of pathogenic variants.

Whole exome sequencing identified pathogenic variants in 9 probands from 23 pedigrees affected by familial dominant cataracts (39%) in CRYAA, CRYBB1, CRYBB3, CRYGC, CRYGD, GJA8 and MIP (Reis et al. 2013. PubMed ID: 23508780). Screening in 25 Chinese families with congenital cataracts identified pathogenic variants in 10 families (40%) in 12 genes encoding crystallins (CRYAA, CRYAB, CRYBA1, CRYBB1, CRYBB2, CRYBB3, CRYBA4, CRYGS, CRYGC, CRYGD), and connexins (GJA3 and GJA8). Approximately 32% of the families had pathogenic variants in crystallin genes and 8% of the families had pathogenic variants in connexin genes (Sun et al. 2011. PubMed ID: 21866213). In another study it was reported that the pathogenic variant detection rate is about 73% in the familial cases (16/22), and 68% in the sporadic cases (17/25). In the same study, ~61% of the pathogenic variants were in crystallin and gap junction genes (Ma et al. 2016. PubMed ID: 26694549).

To our knowledge, no studies have indicated what percentage of the cataract population has copy number variants or which genes have a high frequency of deletion/duplication.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 99.5% coverage of all coding exons of the genes 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 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).