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Glaucoma Genetics

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There are many inheritable forms of glaucoma, both primary and secondary. While inheritance patterns and genetics are not perfectly mapped out for glaucoma, there are some basic observations that can help us screen for glaucoma among family members:

  • Many cases have an autosomal dominant inheritance pattern.
  • There is incomplete penetrance.
  • Environmental factors play a large role in the expression of glaucoma.
  • Family history is a risk factor for the development of primary open angle glaucoma (POAG).
  • 10% of glaucoma patients have siblings with glaucoma.

Glaucoma Genes

There are many genes that have been identified in various forms of glaucoma. While genetic testing for glaucoma is not commonplace, many of these genetic markers do provide some insight into the different mechanisms and components that affect the phenotype we call glaucoma.

While this list is not comprehensive, it highlights a few of the key genotypes that we know contribute to the formation of glaucoma.

Open Angle Glaucomas (GLC1)

Many of the open angle glaucoma genes carry the GLC1 designation, with subtypes lettered following GLC1: GLC1A, GLC1B, etc. This nomenclature may help make it a bit easier to remember what type of glaucoma a particular gene encodes for. As of the American Academy of Ophthalmology's 2016-2017 Basic and Clinical Science Course publication, there are genes listed for GLC1A-GLC1K.

Primary Open Angle Glaucoma

GLC1A (TIGR/MYOC)

The GLC1A gene, which is also called the Trabecular meshwork Inducible Glucocorticoid Response/MYOCillin gene (TIGR/MYOC), encodes the TIGR/myocillin protein, which is found within the trabecular meshwork. It was the first gene identified for POAG, and is located on chromosome 1 ("first gene discovered, first subtype [GLC1A], found on chromosome 1").

3% of POAG patients carry the GLC1A gene, and it is transmitted in an autosomal dominant fashion.

GLC1C

The GLC1C gene is found on chromosome 3 ("C is the 3rd letter of the English alphabet, chromosome 3"). It is associated with a late-onset primary open angle glaucoma that causes high pressure and is only moderately responsive to medications.

GLC1G (WDR36)

The GLC1G gene is found on chromosome 5. It is also known as the WDR36 gene.

Normal Tension Glaucoma

There are 2 genes that have been described in normal-tension (low pressure) glaucoma: GLC1B and GLC1E. A helpful mnemonic for remembering these genes is "BE normal," which refers to the subtypes of the two genes, B and E.

GLC1B

The GLC1B gene is located on chromosome 2 ("B is the second letter of the English alphabet, chromosome 2").

GLC1E (OPTN)

The GLC1E gene is located on chromosome 10. It encodes for the optineurin protein, which is why the other designation for this gene is OPTN ("op-ten-neurin" is a way to help remember the chromosome for this gene).

Secondary Open Angle Glaucomas

Pseudoexfoliation glaucoma (LOXL1)

Pseudoexfoliation syndrome (PXE) is a systemic condition in which there is deposition of a fibrillar material throughout the body, especially in the anterior segment, and is the most common secondary open angle glaucoma. It is associated with the LOXL1 gene, located on chromosome 15.

Pigment Dispersion Syndrome (GPDS1)

Pigment dispersion syndrome (PDS) is another fairly common cause of secondary open angle glaucoma most typically found in young myopic males. The GPDS1 gene, located on chromosome 7, is associated with PDS.

Angle Closure Glaucoma (GLC2)

There is a gene associated with primary angle closure glaucoma, termed GLC2. It is found on chromosome 11, and there are several different mutations, resulting in both autosomal dominant and autosomal recessive forms.

Congenital and Pediatric Glaucomas

Congenital Glaucomas (GLC3)

There are many causes of congenital glaucoma, with currently 4 genes identified. These genes all start with GLC3 and are lettered A-D (GLC3A, etc.). Unlike almost all of the rest of the glaucoma genes, which are inherited in an autosomal dominant pattern, congenital glaucoma genes are inherited in an autosomal recessive pattern.

One way to help remember that congenital glaucoma is GLC3 is by remembering that congenital glaucoma presents in a triad of blepharospasm, epiphora, and photophobia.

GLC3A (CYP1B1)

GLC3A has been identified as encoding the CYP1B1 gene and is found on chromosome 2.

GLC3B

GLC3B is found on chromosome 1.

GLC3C and GLC3D

GLC3C and GLC3D are found on chromosome 14.

Pediatric Glaucomas

There are several syndromes that are associated with the presentation of glaucoma in childhood. While many of these conditions are associated with anterior segment dysgenesis, this is not the only pathogenesis for glaucoma in childhood. A few of these conditions are listed here.

Nanophthalmos (NNO1, VMD2, MFRP)

There are several genes associated with the formation of nanophthalmos, all of which are found on chromosome 11. NNO1 and VMD2 are inherited in an autosomal dominant pattern, and MFRP is inherited in an autosomal recessive pattern.

I need to do some more digging, but I believe that the VMD2 gene on chromosome 11 is the same gene associated with Best vitelliform dystrophy of the retina. If so, it's an interesting connection.

Axenfeld-Rieger Syndrome (RIEG1/PITX2, RIEG2, IRID1/FOXC1)

Axenfeld-Rieger syndrome is a spectrum of anterior segment dysgenesis that can be caused by many different genes, all inherited in an autosomal dominant pattern. RIEG1, or PITX2, is found on chromosome 4, RIEG2 is found on chromosome 13, and IRID1, or FOXC1, is found on chromosome 6.

Nail-Patella Syndrome (NPS/LMXB1)

Nail-patella syndrome (NPS) is a rare condition that primarily affects the nails, knees, elbows, and pelvis. However, it has been implicated in childhood glaucoma, and thus has been on the list of conditions associated with glaucoma. The gene associated with nail-patella syndrome is LMX1B, and is found on chromosome 9.

Essentials To Know

Here are some key points to remember:

  • Almost all of the glaucoma genes, with the noted exception of congenital glaucomas, are inherited in an autosomal dominant pattern.
  • Congenital glaucomas (GLC3) and the MFRP variant of nanophthalmos are inherited in an autosomal recessive pattern.
  • Normal tension glaucoma genes are GLC1B and GLC1E ("BE normal").
  • The first gene identified in open angle glaucoma, GLC1A, is located on chromosome 1 and encodes the TIGR/myocillin protein ("TIGR is number 1").

Summary Table

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References and Additional Reading

  1. American Academy of Ophthalmology. Basic and Clinical Science Course, Section 10: Glaucoma. 2016-2017 ed. San Francisco: American Academy of Ophthalmology, 2016:10-11.
  2. Nail-Patella Syndrome. Genetics Home Reference, National Library of Medicine, National Institutes of Health. Website. https://ghr.nlm.nih.gov/condition/nail-patella-syndrome.
  3. Allingham RR, Liu Y, Rhee DJ. The genetics of primary open-angle glaucoma: a review. Exp Eye Res. 2009;88(4):837-844.
  4. Stone EM, Fingert JH, Alward WL, et al. Identification of a gene that causes primary open angle glaucoma. Science. 1997;275(5300):668-670.
  5. Wolfs RC, Klaver CC, Ramrattan RS, van Duijn CM, Hofman A, de Jong PT. Genetic risk of primary open-angle glaucoma: population-based familial aggregation study. Arch Ophthalmol. 1998;116(112):1640-1645.

Do you have any other tips on how to remember glaucoma genetics? Leave a comment or contact us!