Congenital Cataract, Microcornea, and Corneal Opacity (CCMCO) via the PXDN 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 one-tenth of the cases of childhood blindness (Francis and Moore. 2004. PubMed ID: 14743013). Estimated prevalence rate is 1-6 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. PubMed ID: 8724637). PXDN-associated cataracts (Congenital cataract, microcornea, and corneal opacity-CCMCO) has been described as bilateral iris hypoplasia, ectopia lentis, corectopia, ectropion uveae, and cataracts (Cheong et al. 2016. PubMed ID: 27839872).

CCMCO is an autosomal recessive disorder that is caused by pathogenic variants in the PXDN gene. To date, over 10 pathogenic PXDN variants have been reported, which are missense, nonsense, splicing, and small frameshift deletions (Human Gene Mutation Database).

PXDN encodes Peroxidasin, which is an extracellular matrix-associated protein with peroxidase catalytic activity. Peroxidasin is shown to localize to the cornea and lens epithelial layers, and is essential for normal development of the anterior part of the eye and acts to protect the lens, trabecular meshwork, and cornea against oxidative damage (Khan et al. 2011. PubMed ID: 21907015).

Due to the genetic heterogeneity and limited number of cases, predicting clinical sensitivity is challenging. However, PXDN does not appear to be a common cause of congenital cataracts. Analytical sensitivity should be high because all of the pathogenic variants reported are detectable by sequencing.

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