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New Genetic Syndrome Linked to Developmental Delay, Intellectual Disability

Published on April 27, 2020 · Last Updated 3 years 4 months ago


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Andrew Edmondson, MD, PhD, and colleagues identified a new syndrome within the group of congenital disorders of glycosylation.

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Researchers at Children’s Hospital of Philadelphia identified a new genetic syndrome that results from mutations to a gene that affects glycosylation. The novel disorder is linked to developmental delay and intellectual disability.

Congenital disorders of glycosylation are a group of rare genetic disorders that result from deficient glycosylation, which is a process that takes the body’s proteins and modifies them by adding “sugar building blocks” to make them functional. In the new study, Andrew Edmondson, MD, PhD, attending physician in the Metabolic Disease Program and Division of Human Genetics, evaluated patients who had genetic changes in a protein called GALNT2.

The findings appeared in the journal Brain. The study team anticipates their research will pave the way to understand the normal brain biology and function of glycosylation in the general human population.

“Processes of glycosylation are poorly understood, such as how they impact things and where they’re important,” Dr. Edmondson said. “I’m really excited to tease apart the specific function that glycosylation plays.”

Dr. Edmondson and colleagues evaluated seven patients from four families with impaired GALNT2 protein. The researchers used a blood assay to look at a glycosylation target of the GALNT2 protein in those patients’ blood, ApoC-III, and found that they all lacked a particular sugar building block on the ApoC-III protein.

“We found that these patients have very similar medical concerns, including pretty severe developmental delays, where they didn’t develop on time and didn’t develop ability to speak,” Dr. Edmondson said. “They are also shorter than you’d expect for their family. In addition, they have many changes on brain MRI, and they have abnormal blood chemistry, particularly related to glycosylation.”

The researchers also created a mouse model that copied the genetic changes seen in the patients, and found that the mice exhibited similar health and behavioral changes.

The GALNT2 gene comes from a family of 20 different genes, and it was previously thought that any one of those gene family members could take over, if one of the other gene family members was missing. One of the surprising findings of this study, Dr. Edmondson said, is that this is not the case.

“This study has proven that while the gene family can help out with some of the function, each gene also has some specific functions that only they can fulfill,” Dr. Edmondson said. “By not being able to fulfill that function, they can contribute to genetic health problems.”

Human genome sequencing has shown that more than 400 genes are involved in glycosylation, and at least 150 of these genes are known to cause health concerns if they are mutated.

“Every year, there are new genes identified that play a role in congenital disorders of glycosylation,” Dr. Edmondson said. “Medical knowledge is advancing, and we are confident that there are still undiagnosed diseases out there that are caused by defects in glycosylation.”