Keratoconus and Posterior Polymorphous Corneal Dystrophy via the VSX1 Gene

Keratoconus (KC; kerato meaning cornea and conus meaning cone) is a common form of corneal dystrophy. Clinically it is characterized by noninflammatory bilateral progressive protrusion of the cornea and central stroma thinning. These often result in high myopia, irregular astigmatism and impairment of visual acuity. Usually it is evident in the second decade of life and eventually stabilizes in the third and fourth decades. Estimated prevalence of KC in the general population is approximately 1: 2,000. KC is most commonly an isolated disorder, though several reports describe it as syndromic and seen in Ehlers-Danlos, Marfan, Apert, Noonan, and Down syndromes (Rabinowitz 1998; Bisceglia 2005; Espandar and Meyer 2010). KC treatment ranges from simple spectacle correction to corneal transplantation (Krachmer et al. 1984).

Posterior polymorphous corneal dystrophy (PPCD) is rare autosomal dominant disorder of the cornea, which is clinically characterized as a nonprogressive disorder affecting both the corneal endothelium (CE) and Descemet’s membrane. IN PPCD, affected patient's CE is often multi-layered due to the presence of desmosomes, tonofilaments, and microvilli. These abnormal cells retain their ability to divide and spread to the trabecular meshwork. 40% of affected patients develop glaucoma necessitating keratoplasty (Cibis et al. 1977; Gwilliam 2005).

KC is clinically and genetically heterogeneous. Both autosomal recessive and dominant (AR and AD) inheritance patterns have been described. AD inheritance is frequently reported in families, showing incomplete penetrance and variable expressivity. Mutations in the VSX1 (visual system homeobox 1, also known as RINX) gene have been associated with two distinct autosomal dominantly inherited corneal dystrophies; KC and PPCD (described in the clinical features). The VSX1 gene, which is located on chromosome 20p11.2 (Gwilliam 2005), is a member of the “paired-like” homeodomain transcription factors. Members of this family are shown to be essential for craniofacial and eye development (Vincent et al. 2013). VSX1, encodes a pair-like homeodomian protein, expressed in the inner nuclear layer of the adult retina (Hayashi et al. 2000). VSX1 protein has been reported to regulate cone bipolar cell differentiation during embryonic development. VSX1 mutations may cause impaired photopic vision (Ohtoshi et al. 2004; Wheeler et al. 2012). So far, about 15 mutations (Missense/nonsense, splicing and small indels) have been reported in VSX1 that are involved in KC and PPCD (Human Gene Mutation Database).

A VSX1 screening detected causative mutations in 3.1% of KC patients (42/1350) (De Bonis et al. 2011). Another VSX1 mutational analysis detected mutations in 8.7% of Italian KC patients (Bisceglia 2005). Clinical sensitivity cannot be precisely estimated in PPCD patients as it is a rare form of corneal dystrophy. Analytical sensitivity should be high because all mutations reported are detectable by this method. No gross deletions or duplications have been reported so far (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the VSX1 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).