PGmax^TM - Comprehensive Ocular Disorders Panel

The Comprehensive Ocular Disorders Panel is designed to cover all known forms of inherited eye-related disease. Ocular disorders can be subdivided into two broad categories based on the anatomy of the eye: anterior segment dysgenesis disorders (ASDD) and inherited retinal disorders (IRD).

ASDDs are characterized by abnormalities of the iris, cornea, lens, and trabecular meshwork which can result in the clinical features of aniridia, cataracts, and glaucoma (Ito and Walter. 2014. PubMed ID: 24433355). ASDDs can be both non-syndromic and syndromic (Axenfeld-Rieger, Peters Plus, Alagille, etc.). General abnormalities of the anterior segment can be very common in the population, and approximately 50% of all ASDD cases will develop glaucoma (Alward. 2000. PubMed ID: 11004268).

IRDs are characterized by the progressive loss of photoreceptors in the retina. Approximately 50% of IRDs are clinically defined as retinitis pigmentosa (RP). The clinical features of RP follow the progressive pattern of nyctalopia (night blindness), then peripheral visual field loss (tunnel vision), and finally central vision loss and blindness (Fahim et al. 2017. PubMed ID: 20301590). IRDs can be both non-syndromic and syndromic (Usher, Bardet-Biedl, Alstrom etc.). IRDs are a leading cause of blindness with an estimated incidence of 1 in 1,000-3,000 (Hanany et al. 2020. PubMed ID: 31964843).

Both ASDD and IRD are clinically heterogeneous in disease severity and age of onset. Additionally, genetically distinct eye disorders can often present with overlapping clinical features, making it difficult to diagnose a patient based solely on clinical observations. The Comprehensive Ocular Disorders Panel has the advantage of testing all genes associated with eye disorders for patients with broad or non-specific ocular phenotypes. A molecular diagnosis can guide treatment including emerging gene therapies (Martinez Velazquez and Ballios. 2021. PubMed ID: 34768969; Patel et al. 2018. PubMed ID: 30855774).

This panel includes ~600 genes that have been associated with ocular disorders. Variants in these genes cause disease through all modes of inheritance including autosomal dominant, autosomal recessive, and X-linked. Molecular diagnosis in patients can be further complicated by variable expressivity, incomplete penetrance, and genetic modifiers.

The most common genes involved in anterior segment dysgenesis include PAX6, FOXC1, and PITX2 (Ito and Walter. 2014. PubMed ID: 24433355). The most common genes involved in inherited retinal disorders include PRPH2, ABCA4, RS1, RHO, USH2A, RPGR, and MYO7A (Perea-Romero et al. 2021. PubMed ID: 33452396). However, there are many genes that cause eye disorders in a very small percentage of cases.

See individual gene summaries for information about the molecular biology of gene products and spectra of pathogenic variants.

A study testing for 429 genes (referred to as the oculome) in a large cohort of patients with undiagnosed eye disorders found a definitive diagnosis in ~25% of cases (Patel et al. 2019. PubMed ID: 30653986). Another large cohort study of the eyeGENE network, an initiative of the NIH, found that a pathogenic or likely pathogenic variant was found in 62% of patients with a clinically diagnosed eye disorder (Goetz et al. 2020. PubMed ID: 32893963). These positive results were most commonly identified in ABCA4, USH2A, RPGR, and CHM; however, all together there were ~200 genes identified as diagnostic in the cohort, highlighting the genetically heterogeneous nature of eye disorders. This study also estimated that after genetic testing over 1,000 of the patients qualified to participate in one of the many clinical trials that are ongoing for treatment of eye disorders.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 98.8% coverage of all coding exons of the genes 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 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).