18.4.2  Anterior Segment Dysgenesis

Syndromes

A major concern in families with disease caused by mutations in FOXC1, PITX2, PAX6, and LMX1B is the variable expression of the disease phenotype even within families with the same mutation. Mildly affected family members who are mutation carriers are at risk of transmitting the mutation to their offspring who may then develop severe disease. As very little is understood about the variable expressivity of the phenotype, it is not currently possible to predict the severity of phenotype in the offspring of mutation carriers. Counseling can be difficult in these families because those members who are mutation carriers with mild disease need to understand that 50% of their offspring can inherit the mutation and that their offspring may develop severe, or disease.

18.4.3  Juvenile-Open Angle Glaucoma

Mutations in MYOC that cause juvenile onset glaucoma are transmitted as an autosomal dominant trait. Individuals who carry mutations should be advised that 50% of their offspring are at risk for developing severe glaucoma.

18.4.4  Congenital Glaucoma

For families with mutations in CYP1B1 it is important to test all family members so that mutation carriers can be identified. These individuals need to be counseled that they have a 25% risk of having an affected child if their mate is also a mutation carrier. Mutation testing should be offered to prospective mates. In families with a history of consanguinity this risk may be higher.

18.4.5  Low-Tension Glaucoma

If the OPTN E50K mutation is identified in a family, mutation carriers should be advised that they have a 50% chance of transmitting the mutation to their offspring. These individuals should be followed carefully

for the development of optic nerve disease and visual field changes.

18.4.6  Primary Open-Angle Glaucoma

(Adult-Onset)

If a MYOC mutation is found in a POAG family they should be advised that affected members have a 50% chance of transmitting the disease to offsprings.

18.4.7  Genotype/Phenotype

Correlations

Most of the mutations in genes currently known to contribute to glaucoma have not been correlated with specific clinical outcomes. However, several mutations in MYOC, the gene coding for myocilin, are known to be associated with this severe disease with an early onset of this disease. These mutations include the PRO370LEU (amino acid proline at protein position 370 changed to amino acid leucine) and TYR437HIS (tyrosine amino acid at protein position 437 replaced by amino acid histidine). Carriers of these mutations nearly always require surgery for control of intraocular pressure [20]. In addition, several mutations in MYOC have been shown to be more likely to cause mild disease, including the GLN368STOP (glutamine at protein position 368 replaced by a stop codon) mutation, which is the most common MYOC mutation [21]. Individuals with these mutations may be successfully treated with topical medications. Interestingly,­ one MYOC mutation, Thr377Met (threonine at protein position 377 replaced by amino acid methionine), is frequently associated with hearing loss [22].

Summary for the Clinician

››Glaucoma gene testing can help patients and their families understand their disease risk.

››Genetic counseling for patients and families affected by anterior segment dysgenesis syndromes needs to include an explanation of the variable expressivity of the disease phenotype in these patients.