Summary: Researchers have identified a previously unknown rare genetic disease named RPN1-CDG. The study used whole exome sequencing to pinpoint a mutation in the RPN1 gene in two siblings with an undiagnosed neurodevelopmental disorder.
The mutation interferes with glycosylation, the critical process of attaching sugar chains to proteins, leading to cellular malfunction. This discovery expands the family of Congenital Disorders of Glycosylation (CDG), which now includes over 190 distinct conditions.
Key Facts
- The “Sugar Chain” Essential: Glycosylation is required for most secreted proteins to fold properly and remain stable; without these sugar chains, organ systems throughout the body malfunction.
- Siblings Study: The discovery began with the genomes of two affected siblings. The mutation was absent in their three healthy siblings and had never been recorded in global public genetic databases.
- Expanded Genetic Map: RPN1-CDG is now the eighth gene associated with diseases of the OST complex.
- Broad Symptoms: Because the OST complex is involved in nearly every developmental process, the disease manifests as a range of neurodevelopmental and multi-organ issues.
- Diagnostic Breakthrough: Identifying RPN1-CDG allows doctors to provide definitive answers to other families worldwide whose children may be suffering from the same rare, previously unnamed condition.
Source: Sanford Burnham Prebys
Scientists at Sanford Burnham Prebys Medical Discovery Institute and an international team of collaborators used a genetic sequencing technique called whole exome sequencing to discover a new rare genetic disease.
The researchers published findings April 3, 2026, in Human Genetics and Genomics Advances that identify the faulty mutated gene. By exploring the biochemical consequences of the mutation, the investigators also showed that this typo in the genetic code interferes with normal cellular function, as expected of an unknown congenital disorder of glycosylation (CDG).
CDG is an umbrella term for more than 190 disorders caused by mutations that impair glycosylation, which is the complex process by which cells build long sugar chains that attach to proteins creating glycoproteins. These chains of sugars, termed glycans, are found modifying most secreted proteins. They play many important roles such as ensuring proteins are stable and fold properly. enabling them to carry out their biological function.
When glycosylation is impaired, the sugar molecules on many of the body’s proteins are absent or incomplete, leading to serious, often fatal, malfunctions in various organ systems throughout the body. Because glycosylation has many functions, CDGs lead to a range of symptoms and outcomes, and the diseases require biochemical testing and genome sequencing to deliver a precise diagnosis—or to discover for the first time.
In the new study, the scientists began by sequencing the genomes of two siblings suffering from an unfamiliar neurodevelopmental disorder. They found a mutation shared by the two affected siblings but not by three other siblings showing no signs of the disease. The genetic error had not been reported in any large public database used by geneticists to share information across the globe to help each other diagnose and study rare diseases.
These results sharpened the scientists’ focus on a mutation in the RPN1 gene. This gene carries the blueprints for building a protein called ribophorin I. Because of this protein’s role in glycosylation, the team conducted a biochemical test used to diagnose patients with CDGs by assessing if proteins are being properly adorned with sugar molecules.
“The glycosylation results from these tests reflected patterns we know well from other CDGs,” said Hudson Freeze, PhD, the William W. Ruch Distinguished Endowed Chair and director of the Sanford Children’s Health Research Center at Sanford Burnham Prebys.
“After confirming that this was a new CDG, the next step was to better understand why it was occurring.”
The protein affected by the newly identified mutation—ribophorin I—is an essential component of the complicated biological machinery responsible for glycosylation. Multiple proteins including ribophorin I combine to form two varieties of a cellular factory known as the oligosaccharyltransferase (OST) complex. These conjoined proteins work in concert to decorate freshly constructed proteins with the appropriate sugar molecules.
The research team found that the mutation lopped off part of ribophorin I, leading to protein instability in the OST complex. The truncation of ribophorin I also caused a unique deficit in one of the two subtypes of OST complex called OST-A. This structural defect caused a reduction in the attachment of sugars to many proteins OST-A is meant to glycosylate.
“Because the OST complex plays a role in every developmental process, that is why we see a range of neurodevelopmental and other developmental issues in CDGs,” said Freeze.
By defining and studying this new disease—now termed RPN1-CDG—the scientists have expanded the number of genes associated with OST complex diseases to eight. A better understanding of the new disorder and all CDGs will help provide definitive diagnoses to more patients suffering from rare diseases.
Funding: The study was supported by the National Institutes of Health, National Institute of Neurological Disorders and Stroke, The Rocket Fund and the Howard Hughes Medical Institute.
Key Questions Answered:
A: Think of sugar chains (glycans) as the “quality control” tags on a factory line. Without them, proteins don’t fold into the right shapes. Since the brain relies on a massive, precise array of stable proteins to build neural connections, a failure in this “cellular factory” hits neurodevelopment the hardest.
A: Extremely rare. It was discovered by looking at just one family where two siblings were affected. Before this 2026 study, the specific genetic error hadn’t even been reported in global databases. However, now that the gene is identified, doctors can screen other “undiagnosed” patients for the same mutation.
A: Currently, there is no cure, but the diagnosis is the first step. By understanding that the OST-A complex is the specific “broken machine,” researchers can begin looking for targeted therapies, like metabolic supplements or gene therapies, to bypass the defect.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this genetics and neurodevelopment research news
Author: Greg Calhoun
Source: Sanford Burnham Prebys
Contact: Greg Calhoun – Sanford Burnham Prebys
Image: The image is credited to Neuroscience News
Original Research: Open access.
“A Homozygous Nonsense Variant in the Oligosaccharyltransferase Complex Gene, RPN1, Causes a Congenital Disorder of Glycosylation” by Bobby G. Ng, Wenyue Zhang, Jennifer E. Neil, Marwa Danish, Dana Marafi, Tarek M.
Kamal, Laila Bastaki, Muna Al Saffar, Edward Yang, Miao He, Christopher A. Walsh,
Ganeshwaran H. Mochida, Hudson H. Freeze. Human Genetics and Genomics Advances
DOI:10.1016/j.xhgg.2026.100604
