X-linked Megalocornea 1 (MGC1) via the CHRDL1 Gene

X-linked megalocornea (MGC1) is a nonprogressive bilateral anterior segment dysgenesis of the eye with normal anterior chamber angles, intraocular pressure and axial lengths. This indicates that megalocornea and primary congenital glaucoma are two distinct clinical entities (Kraft et al. 1984; Ho and Walton 2004). However, the MGC1 patients have an increased risk of developing glaucoma (Meire and Delleman 1992). MGC1 is clinically characterized by increased bilateral cornea diameter (greater than 12.5 mm) and a deep anterior chamber, which is evident at birth, and later onset of mosaic corneal degeneration (shagreen), corneal arcus juvenilis, and presenile cataracts (Mackey et al. 1991; Meire et al. 1991). Secondary complications include astigmatic refractive errors, miosis, atrophy of the iris stroma, iridodonesis, and subluxation of the lens (Webb et al. 2012).

Chordin-like 1 gene (CHRDL1) on Xq21.3-q22 (Chen et al. 1989; Meire et al. 1991) is reported to be the only causative gene for X- linked MGC1 (Webb et al. 2012). Female carriers are often asymptomatic (Mackey et al. 1991). CHRDL1 encoded protein ventroptin is shown to be expressed in the developing human cornea and anterior segment of the eye, in addition to the retina, and is required for anterior segment development (Webb et al. 2012). Ventroptin, which is a bone morphogenic protein (BMP) antagonist regulates Bmp4 and Bmp2 signaling the in developing retina and brain and is proposed to have a role in specification of topographic retinotectal projections. Regulation of BMP has been shown to be important for both patterning and control of organ size during embryogenesis (Webb et al. 2012). So far, less than 10 pathogenic sequence variations (including missense, nonsense, splicing, small and gross deletions) in CHRDL1 have been reported in X-linked megalocornea (Human Gene Mutation Database).

Assessment of the X-Linked Megalocornea (MGC1) phenotype in six families showed that all affected male individuals carried mutations in CHRDL1 and female carriers did not show any clinical signs of MGC1. None of the CHRDL1 mutations were detected in 220 control X chromosomes (Webb et al. 2012). Another screening also identified CHRDL1 mutations in all MGC1 affected male individuals and in the heterozygous state in their mother, which was not present in an unaffected brother or in unrelated controls (Han et al. 2013).

This test provides full coverage of all coding exons of the CHRDL1 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).