Homozygosity Mapping of Gene(s) for Congenital Glaucoma

Infantile glaucoma, also called Primary Congenital Glaucoma, is a devastating and potentially blinding disorder of the human eye which appears at or shortly after birth. For reasons not yet understood, 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 clear “watch crystal” on the front of the eye, becomes steamy and hazy, 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 far less than perfect. Infantile glaucoma of this type, as an isolated human disease unassociated with any other birth defects or malformations, is known to be 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 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. There is, however, no way to prove, by any examination or by any test, whether the normal parent, or any normal-appearing individual in the general population is a carrier. Each child of two carrier parents has one chance in four to be affected with congenital glaucoma and two chances in four to be a carrier, just like the parents. Since there is no “test” to identify a carrier for this disease, no test will identify a potentially affected individual before birth or before damage from the disease begins. Infantile glaucoma is more common in the Arab world than in the North-Western Quadrantisphere. One reason for its frequency is 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 cousin, first cousins once removed, or second cousins. At the King Khaled Eye Specialist Hospital in Riyadh, at least one new case of congenital glaucoma is identified and treated each week; the majority are products of consanguineous parents. To identify the genes which cause infantile glaucoma, we propose to map the gene or genes responsible for this disease by analysis of the genetic material (DNA) of consanguineous families (mostly first cousins) with at least one child affected with infantile glaucoma. For various complex biological reasons, the affected child will have inherited two identical regions of the genetic material around and including the gene for congenital glaucoma from each parent, that is the same region which each of them inherited from the common grandparent. In principle, mapping a gene could be achieved with adequate analysis of blood samples from as few as 15 to 30 families of this structure, substantially fewer than the 50 to 75 families with at least three affected children and unrelated parents which the same project would require in the United States, and less than 215 families which were needed to map the gene for the recessive disease cystic fibrosis in North America in 1989. This collaborative project engages an established Genetics Field Team at the King Khaled Eye Specialist Hospital at Riyadh, K.SA, supervised and monitored by Dr. Richard Lewis at Baylor College of Medicine, Houston, and Dr. John Cavender, Director of Research at KKESH. DNA and white blood cells will be analyzed by the modern techniques of molecular genetics in the laboratory of Dr. James Lupski at Baylor. The statistical and computer analyses will be performed by Dr. Jurg Ott, Columbia University. We expect that this project will require at least two years, both to identify, locate, and enroll families with pedigrees most suitable for analysis from all over Saudi Arabia and to perform the necessary thousands of studies on each DNA sample from each person of every family. The ultimate goals are to locate the gene(s) for this disease, to devise techniques for identifying carriers for the disorder for the purposes of genetic counselling, and to provide the tools to encourage investigations of the embryologic abnormalities of development so that better treatments or preventions for this devastating condition can be devised.