Homozygosity Mapping of Gene(s) for Congenital Glaucoma

Infantile Glaucoma, also called Primary Congenital Glaucoma, is a devastating and frequently blinding disorder of the human eye which appears at or shortly after birth. For unknown reasons, the usual channels which allow drainage of the fluids out of the eye develop abnormally in the fetus with this condition. Because the fluids continue to be produced, the pressure inside the eye elevates substantially. As a result, the cornea, the normally clear “watch crystal” on the front of the eye, becomes steamy, both the cornea and other coats of the eye enlarge, and ultimately the optic nerve is damaged, permanently and irreparably destroying vision. Medical treatment for this disease is virtually useless and surgical results are imperfect. Infantile Glaucoma, unassociated with any other birth defects, is known to be transmitted as an autosomal recessive trait. It equally affects boys and girls and, when it occurs in a family, almost always affects siblings rather than parents or offspring. Each (normal appearing) parent of an affected child is presumed to be a “carrier”, that is, to bear within him or her one copy of the “glaucoma-causing” gene and one copy of a “normal” gene. Infantile Glaucoma is more common in the Arab world than in the North-Western Quadrantisphere, in part because of the prevalence of consanguineous marriages, in which the parents are related to one another by descent from a common ancestor. In Saudi Arabia, about 50% of all marriages occur between first cousins, first cousins once-removed, or second cousins. At the King Khaled Eye Specialist Hospital (KKESH) in Riyadh, where at least one new case of congenital glaucoma is identified and treated each week, the majority of cases are products of consanguineous parents. To identify the gene(s) which cause(s) Primary Congenital Glaucoma, we have collected blood samples and extracted the genetic material (DNA) from white blood cells from consanguineous families with at least one affected child. To date, we have collected nineteen families and initiated collections of 43 more. More than 900 DNA samples have been transferred to Houston from Saudi Arabia. Sophisticated technology for simultaneous PCR-based analyses of multiple genetic markers which completely cover Chromosome 14 has been tested, and similar panels for Chromosome 1 and 17 are complete, as are some 300 simple sequence repeat markers throughout the human genome. We analyzed samples with markers on Chromosome 1 recently reported to be linked to autosomal dominant juvenile onset open angle glaucoma. We reject the assignment of Primary Congenital Glaucoma to this region with probabilities greater than 1036. Dr. Lewis has visited Saudi Arabia three times in the past eighteen months to lead a Genetic Research Team to collect the extended families (grandparents, normal siblings, etc.) and to eliminate families with uncertain or confusing diagnoses. Our ultimate goals are to locate the gene(s) for Primary Congenital Glaucoma, to devise strategies to identify carriers for this disorder for the purposes of genetic counselling, and to set the stage for investigations of the abnormalities of embryological development, so that better treatments or preventions of Primary Congenital Glaucoma can be devised. The potential to improve the quality of life for these and other families and the ultimate capacity to modify or to prevent the devastating visual consequences of this disorder in future generations of children have inestimable significance.