Posterior Microphthalmia via the PRSS56 Gene

Posterior microphthalmos (MCOP) is a relatively rare, isolated malformation of the eye. Clinically, MCOP is characterized by extreme hyperopia, retinal folding, normal anterior segment with a small posterior segment, steep corneal curvatures, shallow anterior chamber, thick lenses and scleral wall, reduced visual acuity and strabismic amblyopia. Funduscopy findings include crowded optical discs, tortuous vessels, and an abnormal foveal avascular zone. Affected individuals are at-risk for narrow-angle glaucoma, chorioretinal pathology including uveal effusion and amblyopia due to the abnormally small eye size (Hmani-Aifa et al. 2009; Gal et al. 2011; Said et al. 2013).

To date, pathogenic variants in two genes MFRP (encodes membrane frizzled-related protein) and PRSS56 (encodes a serine protease) have been reported to be causative for autosomal recessive Posterior microphthalmia (arMCOP) (Said et al. 2013).

PRSS56, which encodes a trypsin-like serine protease, is classified as a member of the chymotrypsin family as the encoded protein carries a highly conserved triad consisting of Asp191-His145-Ser286 (similar to trypsin triad Asp102-His57-Ser195), which is required for the catalytic activity of the protein (Gal et al. 2011).

MCOP was found to be highly prevalent in the Faroe Islands due to a founder effect (carrier frequency 3.2%). Patients of the Faroese families were either homozygous for c.926G>C (p.Trp309Ser) or compound heterozygous for c.926G>C and c.526C>G (p.Arg176Gly) variants in PRSS56. Molecular modeling of the p.Trp309Ser variant showed substantially reduced enzyme affinity and reactivity toward in vivo protein substrates. A homozygous single nucleotide deletion c.1066dupC was identified in five arMCOP patients from a consanguineous Tunisian family, which is predicted to result in translational frameshift and protein truncation (p.Gln356Argfs*148). In the Saudi population, PRSS56 pathogenic variants were shown to be the major cause of arMCOP (Orr et al. 2011; Gal et al. 2011; Said et al. 2013; Nowilaty et al. 2013). So far, over 20 pathogenic variants (missense variants and single nucleotide duplications) have been reported in the PRSS56 gene, which the majority are missense variants (90%) (Human Gene Mutation Database; Orr et al. 2011; Gal et al. 2011).

In a mutational screening of 25 MCOP affected patients from 13 families, 19 Saudi patients (~75%) were homozygous for PRSS56 mutations, 1 Indian and 1 Saudi patient had mutations in MFRP, and in 4 Saudi patients no causative variants were detected. All patients had a similar phenotype (Nowilaty et al. 2013).

This test provides full coverage of all coding exons of the PRSS56 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).