specificity required for a gene-based diagnostic or screening test.

18.1.6  Pseudoexfoliation Glaucoma

Recently, DNA sequence variants causing missense amino acid changes in LOXL1 have been found to be significantly associated with pseudoexfoliation glaucoma [2–5]. Although these DNA sequence variants have a very high frequency in the affected population (98%), they are also found in a significant percentage of individuals without pseudoexfoliation (50%). Thus, a test based on these results would have high sensitivity but low specificity, making it less useful, clinically.

Summary for the Clinician

››Ten genes have been shown to contribute to various forms of glaucoma.

››Most of the current glaucoma genes are responsible for early onset forms of glaucoma.

››A good gene-based test has the same sensitivity and specificity expected for other types of clinical tests.

››Current genetic tests are based on direct gene sequencing and are available for: Juvenile onset open-angle glaucoma (MYOC); Axenfeld–Rieger syndrome and other forms of anterior segment dysgenesis (FOXC1, PITX2, PAX6, LMX1B); congenital glaucoma (CYP1B1); familial low-tension glaucoma (OPTN E50K).

18.2.1  Anterior Segment Dysgenesis

For patients affected with conditions causing abnormal development of the ocular anterior segment, genetic testing can be very useful, especially if other members of the patient’s family are affected and the inheritance pattern is consistent with an autosomal dominant trait. As there is significant phenotype overlap between these conditions, one family member (typically the proband) is tested for mutations in all four of the genes currently known to be associated with these syndromes (FOXC1, PITX2, PAX6, and LMX1B). Clinical features can be very helpful in prioritizing the order of testing: small or nonexistent iris would indicate PAX6 testing prior to the other genes, absence of the patella or nail abnormalities would indicate the nail-patella syndrome and suggest testing of LMX1B first. Once a gene defect is found in one member of the family, the entire family, both affected and unaffected members, should be screened. Given the well-documented variable expressivity of mutations in these genes, unaffected family members may actually be gene mutation carriers.

18.2.2  Juvenile-Onset Open-Angle

Glaucoma

Families with autosomal dominant inheritance of early onset glaucoma without evidence of anterior segment dysgenesis can be tested for mutations in MYOC, the gene coding for myocilin. Approximately 20% of these families will have a MYOC mutation, which can be associated with severe glaucoma that typically requires surgical treatment [17].

18.2  Are Genetic Tests for Glaucoma of Practical Use in a Clinical Setting Today, or Are They More of Theoretical Use?

Currently, glaucoma genetic testing is most useful for families with early-onset forms of glaucoma. Genetic testing may be useful in some cases of adult-onset primary­ open angle glaucoma caused by mutations in MYOC. General guidelines for testing are described below.

18.2.3  Congenital Glaucoma

Patients with a family history consistent with autosomal recessive congenital glaucoma should be screened for mutations in CYP1B1, especially if there is a family history of consanguinity. In small families, autosomal recessive traits may appear as isolated traits, so “sporadic” cases of congenital glaucoma should also be screened for mutations in this gene. If a mutation is found, all family members should be screened to detect individuals who may be unaffected carriers.