Glaucoma Panel

Glaucoma is a major cause of blindness worldwide. Glaucoma is characterized by elevated intraocular pressure (IOP), increased corneal diameter (megalocornea), enlarged globe (buphthalmos), Haab’s striae (opacification of the cornea with ruptures involving Descemet’s membrane), corneal edema and optic nerve head cupping, thinning of the anterior sclera and atrophy of the iris. Symptoms include photophobia, blepharospasm (abnormal contraction of the eyelid), and hyperlacrimation (excessive tearing). Abnormal development of the anterior segment angle or goniodysgenesis are the hallmarks of congenital glaucoma (Abu-Amero et al. 2011. PubMed ID: 22128238).

Primary congenital glaucoma (PCG) or Trabeculodysgenesis presents in neonates and during the infantile period with a varying prevalence rate ranging from 1 in 1,250 to 20,000 among different geographic locations and ethnic groups. The highest prevalence is found in the Gypsy population of Slovakia (1 in 1,250) followed by Saudi Arabians (1:2,500), Southern India (1:3,300), and the Western nations (1:5000-22,000) (Gencik et al. 1982. PubMed ID: 7173860; Azmanov et al. 2011. PubMed ID: 21081970; Abu-Amero. 2011. PubMed ID: 22128238).

Adult-onset Primary open-angle glaucoma (POAG) is the most common subtype affecting all ages, for which there is currently no cure, only treatments that may slow its progress. Early detection is needed in order to prevent vision loss (Martin et al. 2000. PubMed ID: 10851252; Abu-Amero. 2011. PubMed ID: 22128238).

With the advent of gene therapy and other types of treatments, the identification of causative genes and variants is becoming increasingly important.

Please see the following links for clinical trials and management options:

https://medlineplus.gov/glaucoma.html

Glaucoma Clinical trials

Pathogenic variants in CYP1B1, and LTBP2 have been reported to cause primary congenital glaucoma with autosomal recessive inheritance (Abu-Amero. 2011. PubMed ID: 22128238). A study indicated that the CYP1B1 c.182G>A (p.Gly61Glu) variant was seen in 78% of the PCG chromosomes analyzed and reported as a common mutation in Saudi Arabian population (Bejjani et al. 1998. PubMed ID: 9463332, reported as 3987G>A change). CYP1B1 c.1159G>A (p.Glu387Lys) is a common pathogenic variant in Slovak Gypsies (Roms) due to a founder effect (Plásilová et al. 1999. PubMed ID: 10227395). Both these variants are reported at ~0.003% in the general population (https://gnomad.broadinstitute.org/variant/2-38302350-C-T; https://gnomad.broadinstitute.org/variant/2-38298338-C-T).

Juvenile-onset POAG exhibits autosomal dominant inheritance and is due to heterozygous pathogenic variants in MYOC, OPTN, TEK or WDR36. Adult-onset POAG is generally inherited as a complex trait with multigenic inheritance (Ray and Mookherjee. 2009. PubMed ID: 20090207; Carnes et al. 2014. PubMed ID: 24875647). Approximately 10%–20% of adult-onset POAG cases are due to monoallelic pathogenic variants in the MYOC gene (Khan. 2011. PubMed ID: 21730848; Wiggs et al. 2004. PubMed ID: 15108121).

Glaucoma is manifested in several syndromic disorders associated with anterior segment dysgenesis. Examples include Nail-patella syndrome, Axenfeld-Rieger syndrome, Aniridia, nanophthalmos, and Frank-ter Haar syndrome. Causative variants in LMX1B (Vollrath et al. 1998. PubMed ID: 9618165), PITX2 (Strungaru et al. 2007. PubMed ID: 17197537), FOXC1 also known as FKHL7 (Ito et al. 2014. PubMed ID: 24556684; Paylakhi et al. 2013. PubMed ID: 23541832), FOXE3 (Semina et al. 2001. PubMed ID: 11159941), PAX6 (Tzoulaki et al. 2005. PubMed ID: 15918896), MAF (Anand et al. 2018. PubMed ID: 29314435) and COL4A1 (Sibon et al. 2007. PubMed ID: 17696175) are inherited in an autosomal dominant manner. Causative variants in MFRP (Ayala-Ramirez et al. 2006. PubMed ID: 17167404), SH3PXD2B (Iqbal. 2010. PubMed ID: 20137777), SLC4A4 (Igarashi et al. 1999. PubMed ID: 10545938), SIX6 (Carnes et al. 2014. PubMed ID: 24875647) and ATOH7 (Prasov et al. 2012. PubMed ID: 22645276) are inherited in an autosomal recessive manner. The mode of inheritance for OPTC (Acharya et al. 2007. PubMed ID: 17359525), COL8A2 and COL8A1 (Desronvil et al. 2010. PubMed ID: 21139683) is currently unknown.

Of note, de novo variants in MYOC and FOXC1 have been documented to be causative for glaucoma (Kuchtey et al. 2013. PubMed ID: 23517641; Wiggs and Pasquale. 2017. PubMed ID: 28505344).

Human and experimental models suggest that elevated intraocular pressure (IOP) obstructs retrograde and anterograde axonal transport of neurotrophins in retinal ganglion cells (RGCs) and results in RGCs axon damage within the optic nerve head (ONH) (Stowell et al. 2017. PubMed ID: 28223180; Chitranshi et al. 2018. PubMed ID: 29676228).

A wide variety of causative variants (missense, nonsense, splicing, small deletions and insertions) have been reported in these glaucoma-associated genes, including large deletions/duplications and complex genomic rearrangements in a few genes (FOXC1, PAX6, CYP1B1, PITX2, LMX1B, SHH, MAF, TEK and ATOH7) (Human Gene Mutation Database). All documented large deletions in OPTN have been reported in amyotrophic lateral sclerosis patients, while none have been reported in glaucoma patients (Human Gene Mutation Database).

See individual gene summaries for more information on molecular biology of gene products and spectra of pathogenic variants.

Abu-Amero et al. detected CYP1B1 pathogenic variants in 76% of families (41 out of 54) with at least one affected member with primary congenital glaucoma (PCG) (Abu-Amero. 2011. PubMed ID: 22128238). Another molecular analysis of CYP1B1 identified three pathogenic variants in 78% (7/9) of the unrelated PCG index cases (El-Gayar et al. 2009. PubMed ID: 19597567). Approximately 10%–20% of adult-onset primary open-angle glaucoma (POAG) cases are due to pathogenic variants in the MYOC gene (Khan. 2011. PubMed ID: 21730848; Wiggs et al. 2004. PubMed ID: 15108121). Another study reported that 3.6% (9/251) of the POAG patients had pathogenic variants in the CYP1B1, MYOC, and OPTN genes (Kumar et al. 2007. PubMed ID: 17563717).

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

This panel typically provides 97.6% 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).