Scientists use whole exome sequencing to discover a new rare genetic disease

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." 

Hudson Freeze, PhD, the William W. Ruch Distinguished Endowed Chair and director of the Sanford Children's Health Research Center at Sanford Burnham Prebys

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.