Familial normal- tension glaucoma (NTG) is associated with mutations in optineurin (OPTN) and copy number variations involving TANK- binding kinase 1 (TBK1). These genes encode proteins that interact with each other and are involved in autophagy. These ge ne tic abnormalities are associated with early- onset autosomal dominant familial NTG and account for approximately 2%–3% of cases.

Primary congenital glaucoma (PCG) is rare, but it represents the most common form of childhood glaucoma, with an incidence ranging from 1:1250 to 1:10,000 depending on the population studied. Although most cases are sporadic, a large proportion is inherited. Disease- causing mutations have been identified in 4 genes. Recessive mutations in the gene encoding cytochrome P-450 1B1 (CYP1B1) are the most common cause of PCG identified to date. Cytochrome P-450 1B1 appears to be required for trabecular meshwork development and function. Recessive mutations in latent transforming growth factor β- binding protein 2 (LTBP2) also cause PCG. The gene encodes a protein associated with microfibrils, cell adhesion, and maintenance of the extracellular matrix. Other ophthalmic diseases associated with LTBP2 mutations include Weill- Marchesani syndrome, microspherophakia, and ectopia lentis. Disease- causing mutations in tunica interna endothelial cell kinase (TEK, also known as TIE2) and angiopoietin 1 (ANGPT1) genes result in maldevelopment of the Schlemm canal in mouse models and are inherited as a dominant trait with variable expressivity in some patients with PCG.

Axenfeld- Rieger syndrome includes a spectrum of abnormalities of ocular and systemic development, often associated with glaucoma. Linkage analy sis has led to the discovery of autosomal dominant mutations in 2 genes, paired- like homeodomain transcription factor 2 (PITX2) and forkhead box C1 (FOXC1). Both genes encode transcription factors that regulate embryonic development.

Aniridia, another ocular developmental disorder, is frequently associated with glaucoma. It occurs in an autosomal dominant inheritance pattern or sporadically. The autosomal dominant form is associated with missense mutations in paired box gene 6 (PAX6), whereas the sporadic form is associated with large deletions or rearrangements involving the same gene, which encodes a transcription factor impor tant for ocular development. Sporadic cases of aniridia caused by large deletions of chromosome 11p13, which includes PAX6, can cause a syndrome comprising Wilms tumor, aniridia, genitourinary anomalies, and mental retardation (WAGR syndrome). Patients with large deletions that involve the closely linked Wilms tumor suppressor gene (WT1) are at risk for developing Wilms tumor. Therefore, persons with sporadic aniridia should be tested for 11p13 deletions to determine if screening for Wilms tumor is required.

The more common adult- onset forms of glaucoma are generally associated with complex ge ne tic inheritance patterns. Genome- wide association studies (GWAS) have been used to identify many ge ne tic loci associated with POAG, 8 with PACG, and 2 with pseudoexfoliation syndrome. GWAS have also led to the discovery of ge ne tic risk alleles for IOP and certain glaucomatous optic nerve features.

Pseudoexfoliation syndrome is characterized by the presence of an abnormal fibrillar material that can be visualized on vari ous structures in the anterior segment. Disease-associated ge ne tic variants in lysyl oxidase like 1 (LOXL1) are pre sent in up to 99% of cases and 80% of controls. This enzyme is involved in elastin metabolism. The abnormal fibrillar material may impair aqueous humor outflow. In addition, elastin is an impor tant component of the lamina cribrosa, where an abnormality in elastin function may result in increased susceptibility to injury. Other factors, including environmental factors such as sun exposure and low ambient temperature, are thought to contribute to the risk of developing the disease.

Ge ne tic counseling and diagnostic testing are impor tant for patients with early- onset glaucoma or ocular developmental abnormalities associated with a high risk of developing glaucoma. Testing for disease- causing mutations in the genes listed in Table 1-2 can be useful to determine patterns of inheritance, identify children at risk early in the disease course, and estimate risk to future offspring.

Lewis CJ, Hedberg- Buenz A, DeLuca AP, Stone EM, Alward WLM, Fingert JH. Primary congenital and developmental glaucomas. Hum Mol Genet. 2017;26(R1):R28– R36.

Evidence that environmental factors can play a role in the etiology of glaucoma arises from studies of twins in which the disease was not uniformly manifest in monozygotic twins. These data suggest that while ge ne tic factors contribute to the development of glaucoma, environmental and behavioral factors are also impor tant. Through the use of longitudinal epidemiologic studies (eg, the TwinsUK Registry, the United States Department of Veterans Affairs Normative Aging Study, and the Nurses’ Health Study), a number of environmental factors have been identified that possibly modulate the risk for glaucoma. These factors include sun and low ambient temperature exposure (for pseudoexfoliation syndrome), estrogen exposure, cholesterol levels and statin use, and lead exposure.

Stein JD, Pasquale LR, Talwar N, et al. Geographic and climatic factors associated with exfoliation syndrome. Arch Ophthalmol. 2011;129(8):1053–1060.