Does consanguinity increase the risk of primary congenital glaucoma, and what is the underlying genetic mechanism?

Does Consanguinity Play a Role in Congenital Glaucoma Development?

Yes, consanguinity is strongly associated with primary congenital glaucoma (PCG) and significantly increases disease risk through autosomal recessive inheritance patterns, with CYP1B1 gene mutations being the primary genetic mechanism. 1, 2

The Genetic Mechanism

Primary congenital glaucoma follows an autosomal recessive inheritance pattern, making consanguineous marriages a major risk factor. 1 The disease is highly prevalent in inbred populations precisely because both parents are more likely to carry the same recessive mutation when they share common ancestry. 1, 2

CYP1B1: The Primary Culprit

• CYP1B1 gene mutations on the GLC3A locus are the most common identifiable cause of autosomal recessive primary congenital/infantile glaucoma. 3, 4
• The mutation spectra vary widely across different populations but are well-structured based on geographic and haplotype backgrounds. 1
• Multiple novel mutations have been identified in consanguineous families, including L177R, L487P, D374E, and E229K variants that segregate with the disease phenotype. 5

Why Consanguinity Matters Mechanistically

In consanguineous populations, both parents are more likely to be heterozygous carriers of the same CYP1B1 mutation, creating a 25% risk with each pregnancy that a child will inherit two copies of the defective gene and develop PCG. 1, 2 This explains why PCG clusters dramatically in families with consanguineous marriages compared to outbred populations.

Clinical Implications for Genetic Counseling

Variable Expressivity Creates a Counseling Challenge

• Seemingly unaffected siblings of children with CYP1B1-related PCG should undergo genetic testing because of variable expressivity for the phenotype. 3
• Such testing should also be considered for other asymptomatic relatives, especially in consanguineous families. 3
• The severity of abnormality varies according to the stage at which arrested development of neural crest tissues occurred in the third trimester. 2

Additional Genetic Loci

• Beyond CYP1B1, three other chromosomal loci have been identified: GLC3B, GLC3C, and GLC3D (harboring LTBP2). 1, 3
• LTBP2 mutations can cause congenital/infantile glaucoma with a phenotypic spectrum including primary megalocornea and spherophakia with ectopia lentis. 3

Practical Counseling Algorithm for Consanguineous Families

When counseling consanguineous couples with a family history of PCG:

1. Explain the 25% recurrence risk with each pregnancy if both parents carry the same CYP1B1 mutation. 1, 2
2. Offer genetic testing to identify the specific mutation in the affected proband first. 4
3. Test both parents for carrier status once the familial mutation is identified. 4
4. Screen all siblings of affected children, even if asymptomatic, due to variable expressivity. 3
5. Provide prenatal genetic counseling for future pregnancies with options for prenatal diagnosis. 4

Common Pitfalls to Avoid

• Do not assume unaffected siblings are genetically clear—they may carry two mutations with minimal phenotypic expression. 3
• Do not limit genetic testing to the proband alone in consanguineous families; extended family screening is critical. 3, 4
• Remember that CYP1B1 mutations can infrequently underlie juvenile and even primary adult-onset open-angle glaucoma, particularly in consanguineous populations. 3