Scientists find out new genetic mutation responsible for childhood glaucoma

An international team led by Mass Eye and Ear, a member of Mass General Brigham and Boston Children's Hospital, has discovered a new genetic mutation that could be the root cause of severe cases of childhood glaucoma, a devastating condition that runs in families and can rob children of their vision by the age of three. Using modern genome-sequencing technology, the researchers detected a mutation in the thrombospondin-1 (THBS1) gene in three ethnically and geographically varied families with a history of childhood glaucoma. The findings were subsequently validated in a mouse model with the genetic mutation that acquired glaucoma symptoms due to a previously unknown disease mechanism.

This pressure increase not only harms the optic nerve but can also harm other components in a child's eye, such as the cornea. Children with childhood glaucoma often require surgery as early as three to six months of life, followed by a series of additional operations throughout their youth. There is generally a strong genetic component to childhood glaucoma, with numerous members of a family affected by the ailment. According to Dr Wiggs, genetic testing can provide affected families with peace of mind by determining whether their child is at risk of developing the disease.

Uncovering the genetic underpinnings of disease: The new findings, published in the Journal of Clinical Investigation, could lead to improved screening for childhood glaucoma and earlier and more targeted treatments to prevent vision loss in children with the mutation, according to the study's authors. "This is a very exciting finding for families affected by childhood glaucoma," said Janey L. Wiggs, MD, PhD, Associate Chief of Ophthalmology Clinical Research at Mass Eye and Ear and the Vice Chair for Ophthalmology Clinical Research and Paul Austin Chandler Professor of Ophthalmology at Harvard Medical School. "With this new knowledge, we can offer genetic testing to identify children in a family who may be at risk for the disease and start disease surveillance and conventional treatments earlier to preserve their vision. In the future, we would look to develop new therapies to target this genetic mutation."

Leading cause of childhood blindness: Childhood glaucoma, also known as congenital glaucoma, is a rare but serious disease that can appear in children as young as birth or as old as three years old. Despite its rarity, childhood glaucoma accounts for 5% of all cases of child blindness worldwide. Glaucoma is irreversible damage to the optic nerve of the eye caused by a buildup of pressure inside the eye (intraocular pressure, or IOP). This damage can occur without symptoms in adults, which is why the disease is often referred to as a "sneak thief of sight."

Children and babies with childhood glaucoma, on the other hand, can be born with severe disease and vision loss, or they can lose their vision later in childhood as a result of elevated IOP. For decades, researchers have turned to genetics to learn more about the causes of glaucoma. Dr Wiggs began this line of research 30 years ago when scientists could only identify regions of the genome affected by glaucoma.

Researchers now have the ability to examine the entire genetic makeup of people with and without glaucoma to determine which specific genetic mutations play a role in the disease, thanks to advances in genomic technology. Dr Wiggs' 2021 study used a dataset of over 34,000 adults with glaucoma to identify 127 genes associated with the condition. Dr Wiggs and her Mass Eye and Ear team first examined exome sequences from an American family of European-Caucasian descent who had participated in an earlier research project and discovered a striking and novel variant in thrombospondin-1, a well-known protein in the body involved in a number of important biological processes, including the formation of new vessels (angiogenesis) and tissues. This mutated gene was not discovered in people who did not have childhood glaucoma or in large population genetic databases. The amino acid changed by the mutation was evolutionarily conserved, indicating that it plays a critical role in protein function.

This finding led Dr Wiggs to connect with colleagues at Flinders University in Australia to see if they had any childhood glaucoma families with thrombospondin mutations. They surprisingly found two families with an alteration at the same amino acid: one of mixed European and Indian descent, and one Sudanese family originally from Africa. "What was really striking about this finding is that these families all possessed this genetic variant, and it was not possible for them to be related because they were from such diverse backgrounds," said Dr Wiggs. "That meant there was something really important about this mutation."

To further test this hypothesis, the researchers collaborated with Robert J. D'Amato, MD, PhD, the Judah Folkman Chair in Surgery in the Vascular Biology Program at Boston Children's Hospital, and a professor of Ophthalmology at Harvard Medical School. Dr D'Amato's team developed a mouse model with the THBS1 mutation and found that the mouse also had features of glaucoma. "Thrombospondin-1 is well known as a potent inhibitor of blood vessel growth, or angiogenesis," said Dr D'Amato, who has studied angiogenesis for more than three decades. "I assumed at first that THBS1 mutations were disrupting blood vessel formation in the eye, but our animal models showed normal angiogenesis. We realized that there must be another mechanism."

Specifically, D'Amato's lab showed that the mutation caused abnormal thrombospondin proteins to accumulate in the intraocular drainage structures of the eye involved with regulating IOP, which in turn, led to a buildup of pressure that damaged the optic nerve and led to the loss of retinal ganglion cells, thereby causing vision loss. This was the first time that researchers identified this kind of disease mechanism for causing childhood glaucoma.

"This work highlights the power of international collaborations," said study co-author Owen M. Siggs MD, DPhil, associate professor at Flinders University and the Garvan Institute of Medical Research in Australia. "There's such incredible genetic diversity across the globe, and comparing this information is becoming more and more critical for discoveries like this."