PRSS56

Inheritance Pattern: AR

Disease ID:MONDO:0013293

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0013293

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0013293

Submitter: ClinGen

The *PRSS56* gene was first reported in relation to microphthalmia in 2011, with the identification of homozygous or compound heterozygous *PRSS56* variants in a number of affected individuals including multiple large families (Gal et al., PMID: 21397065, Nair et al., PMID: 21532570, and Orr et al., PMID: 21850159). Affected individuals are generally reported with a diagnosis of posterior microphthalmia or nanophthalmia and exhibit clinical features including short axial length, high hypermetropia, reduced visual acuity, high intraocular pressure, angle closure glaucoma, crowded optic discs, and/or papillomacular fold. Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the molecular mechanism (biallelic loss of function) and mode of inheritance (autosomal recessive) were found to be consistent among patients regardless of diagnosis, while the phenotypic variability between them appeared to represent a spectrum of disease rather than separate disease entities. Therefore, cases caused by inherited *PRSS56* variants have been lumped for curation as a single disease entity, referred to as PRSS56-related nanophthalmos. This curation has scored eight suspected disease-causing variants (three frameshift, four missense, and one canonical splice site disruption), which have collectively been reported in eight probands from six publications (PMID: 21397065, PMID: 21532570, PMID: 21850159, PMID: 23127749, PMID: 31992737, PMID: 33203948). Two of the variants are predicted to trigger nonsense-mediated decay, consistent with a biallelic loss-of-function mechanism of pathogenicity. Co-segregation of the homozygous genotype with affected status in the proband’s family was also incorporated into the genetic evidence component of this curation (PMID: 23127749). Additional genetic evidence was available but not included in this curation. This gene-disease association is also supported by evidence that *PRSS56* is highly expressed in retina, as well as in the testis, muscle and brain (PMID: 30239781). The specific areas of the retina with highest expression are the inner nuclear layer and the ganglion cell layer (PMID: 21532570). Biochemical studies indicate that *PRSS56* encodes a secreted serine protease (PMID: 21532570, PMID: 37400936). This is consistent with electron microscopy results from mice indicating that homozygous *Prss56* loss-of-function results in focal hypoplasia of the trabecular meshwork, reduced collagen fibrils in the trabecular beams, increased occurrence of open spaces lacking extracellular matrix, and foci of collagen fibril crowding in the sclera (PMID: 21532570). Mouse models additionally show short axial eye length, reduced vitreous chamber depth and equatorial diameter, and reduced distance between the retina and Schlemm's canal leading to angle closure, as well as choroidal expansion, anterior chamber enlargement, hyperopia, high intraocular pressure with reduced outflow facility, and glaucomatous nerve damage with optic nerve excavation and nerve fiber layer thinning (PMID: 21532570, PMID: 32152063). In summary, *PRSS56* has definitive evidence of association with PRSS56-related nanophthalmos. This has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence, leading to a Definitive classification. This classification was approved by the ClinGen Glaucoma and Neuro-Ophthalmology Gene Curation Expert Panel on May 15th, 2025 (SOP Version 11).

Inheritance Pattern: AD

Disease ID:MONDO:0005514

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0013293

Submitter: PanelApp Australia