New Genetic Mutation Behind Childhood Glaucoma Identified

Discovery may improve disease screening, personalize treatments

By RYAN JASLOW | Mass Eye and Ear Communications Research

6 min read

Closeup of a baby's face with one eye closed and hand resting on nose
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An international team led by Harvard Medical School scientists at Mass Eye and Ear and Boston Children’s Hospital has discovered a new genetic mutation that may be a root cause of severe cases of childhood glaucoma, a devastating condition that runs in families and can rob children of their vision by 3 years of age.

Through advanced genome-sequencing technology, the researchers found a mutation in the thrombospondin-1 (THBS1) gene in three ethnically and geographically diverse families with childhood glaucoma histories. The researchers then confirmed their findings in a mouse model that possessed the genetic mutation and went on to develop symptoms of glaucoma driven by a previously unknown disease mechanism.

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The new findings, published Dec. 1 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 Wiggs, the HMS Paul Austin Chandler Professor of Ophthalmology at Mass Eye and Ear. “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, or congenital, glaucoma is a rare but serious disease that presents in children as early as birth and as late as 3 years of age. Despite its rarity, childhood glaucoma is responsible for 5 percent of cases of child blindness worldwide.

Glaucoma causes irreversible damage to the eye’s optic nerve, often due to a buildup of pressure inside the eye, called intraocular pressure, or IOP. In adults, this damage can occur over time without symptoms.

Children and babies with childhood glaucoma, however, can be born with severe disease and vision loss or lose their vision later in childhood due to elevated IOP. This increase in pressure not only damages the optic nerve but can affect other structures in a child’s eye, like the cornea. Children with childhood glaucoma typically require surgeries as early as the first three to six months of life, followed by several more operations throughout their childhood.

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With childhood glaucoma, there is typically a strong hereditary component, often with multiple members of a family affected by the condition. According to Wiggs, by better understanding the genes involved, genetic testing can give affected families peace of mind to learn whether their child might be at risk for developing the disease.

Uncovering the genetic underpinnings

For decades, researchers have turned toward genetics to better understand the cause of glaucoma. When Wiggs first began this line of research 30 years ago, scientists were able to identify only regions of the genome affected in glaucoma. Thanks to advances in genomic technology, researchers gained the ability to review the complete genetic makeup of individuals with and without glaucoma to determine which specific genetic mutations play a role in the disease. Research led by Wiggs in 2021 used a dataset of more than 34,000 adults with glaucoma to identify 127 genes associated with the condition.

To better study the genetic mutations in childhood glaucoma, Wiggs and her Mass Eye and Ear team first looked at exome sequences from an American family of European-Caucasian descent who had been part of an earlier research project and found a striking and novel variant in thrombospondin-1, a well-known protein involved in a number of important biological processes, such as the formation of new blood vessels (angiogenesis) and tissues. This mutated gene was not found in people without childhood glaucoma, nor in large population genetic databases. The amino acid altered by the mutation was evolutionarily conserved, indicating an important role in the protein’s function. This finding led Wiggs to connect with colleagues at Flinders University in Australia to see if they had any childhood glaucoma families with thrombospondin mutations. They 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 Wiggs, who is associate chief of ophthalmology clinical research at Mass Eye and Ear. “That meant there was something really important about this mutation.”

To further test this hypothesis, the researchers collaborated with Robert D’Amato, HMS professor of ophthalmology at Boston Children's. 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 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 Siggs of 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.”

Personalizing care for families

The new study has significant clinical implications, according to the researchers. While more work remains before comprehensive genetic testing can be offered, every gene found presents another opportunity to be able to identify causative mutations in these families through screening, according to the authors.

Therapeutically, knowledge of this gene mutation can lead to earlier treatments with conventional therapies. For example, if a baby is born with this mutation, their eye care specialist can better inform the parents of the risks and develop an appropriate disease-monitoring and treatment plan.

Identifying this new mechanism and gene at the root of childhood glaucoma could also lead to new therapies that would target the accumulation of abnormal proteins. The researchers also aim to determine whether other THBS1mutations are involved in adult-onset disease, like primary open-angle glaucoma, or milder forms of the disease.

The researchers will also continue to look for new genes associated with childhood glaucoma in the hopes of one day developing very comprehensive screening.

“Dr. Wiggs is an international expert in glaucoma genetics and has worked tirelessly to unravel the genetic contributions to these blinding diseases. These findings provide important insights into the causes of childhood glaucoma and offer the prospect of targeted therapy,” said Joan Miller, the HMS David Glendenning Cogan Professor of Ophthalmology at Mass Eye and Ear, chair of ophthalmology at Mass Eye and Ear and Massachusetts General Hospital, and ophthalmologist-in-chief at Brigham and Women’s Hospital. “The collaboration is a powerful demonstration of the strength of bedside-to-bench-to-bedside translational research in uncovering disease pathogenesis and developing therapies for patients.”

Co-authors of the study included Haojie Fu, Lachlan Knight, Sandra Staffieri, Jonathan Ruddle, Amy Birsner, E. Ryan Collantes, and Jamie Craig.

This study was funded by the March of Dimes; National Institutes of Health (grants R01EY031820 and P30EY014104); Ophthalmic Research Institute of Australia; Channel 7 Children’s Research Foundation; Department of Innovation, Industry, Science and Research (Australia); National Health and Medical Research Council of Australia; and Boston Children’s Mouse Gene Manipulation Core (funded by NIH/NICHD U54 HD090255 and NIH R01 NS38253).

Adapted from a Mass Eye and Ear news release.