Congenital 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). 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).

Only 10–25% of congenital cataracts are hereditary. Cataracts are most often inherited as an autosomal dominant trait. CC also exhibits autosomal recessive or X-linked inheritance (Hejtmancik 2008). 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; Stambolian et al. 1990).

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).

Pathogenic variants in 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 are inherited in an autosomal dominant manner. Pathogenic variants in AGK, CRYBB3, FYCO1, GCNT2, LIM2, SIL1, TDRD7, BFSP1, PXDN,CTDP1, HYCC1/FAM126A, GALK1, P3H2 and CRYBB1 are inherited in an autosomal recessive manner. Pathogenic variants in NHS gene causes an 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 also possible due to variants in completely different genes (Hejtmancik 2008; Santana and Waiswo 2011; Chen et al. 2011; Pras 2004; Haghighi et al. 2014).

See individual gene test descriptions for information on molecular biology of gene products.

Whole exome sequencing identified pathogenic variants in 9 probands from 23 pedigrees affected by familial dominant cataract (39%) in CRYAA, CRYBB1, CRYBB3, CRYGC, CRYGD, GJA8 and MIP (Reis et al. 2013). Mutation 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).

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/duplications. Copy number variants in AGK, BFSP1, CRYAB, EYA1, HYCC1, GCNT2, HSF4, NHS, PAX6, PITX3 and SIL1 have been reported to be causative to date (Human Gene Mutation Database).

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

This panel typically provides 99.1% 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).