Summary: Researchers have identified a previously unrecognized rare genetic disorder now named RPN1-CDG. Using whole exome sequencing, investigators traced a damaging mutation in the RPN1 gene in two siblings with an undiagnosed neurodevelopmental condition. Biochemical studies showed the mutation disrupts glycosylation—the process of attaching sugar chains to proteins—resulting in widespread cellular dysfunction. This finding expands the spectrum of Congenital Disorders of Glycosylation (CDG), a group that already includes more than 190 distinct conditions.
Congenital Disorders of Glycosylation affect how cells build and attach glycans (sugar chains) to proteins, a modification essential for proper protein folding, stability and function. When glycosylation fails or is incomplete, many secreted and membrane proteins lack the glycans they need, producing multi-organ dysfunction and a variety of clinical features. Because glycosylation underlies many developmental processes, CDGs commonly present with neurodevelopmental abnormalities alongside other systemic problems.
Key Facts
- The role of glycosylation: Glycans are critical quality-control tags that help proteins fold correctly and remain stable; their absence impairs protein function across tissues.
- Family-based discovery: The new disorder was identified after sequencing two affected siblings. The same mutation was not present in three healthy siblings and had not previously been reported in major public genetic databases.
- OST complex involvement: RPN1-CDG is the eighth gene now linked to diseases of the oligosaccharyltransferase (OST) complex, a cellular machine that transfers glycans onto newly made proteins.
- Wide-ranging symptoms: Because OST activity contributes to nearly every developmental process, defects in OST components can produce diverse neurodevelopmental and multi-organ manifestations.
- Diagnostic impact: Naming and characterizing RPN1-CDG enables clinicians to provide definitive diagnoses for other families with similar unexplained conditions and to screen undiagnosed patients for the same defect.
Source: Sanford Burnham Prebys
Study overview: Scientists at Sanford Burnham Prebys Medical Discovery Institute, together with international collaborators, applied whole exome sequencing to find the genetic cause of an unfamiliar neurodevelopmental disorder in a single family. Their results, published April 3, 2026 in Human Genetics and Genomics Advances, pinpoint a homozygous nonsense variant in the RPN1 gene and demonstrate how the mutation alters cellular biochemistry consistent with a congenital disorder of glycosylation.
The investigative team focused on a mutation in RPN1, the gene that encodes ribophorin I, a protein component of the OST complex. The OST complex exists in two subtypes and serves as the enzymatic machinery that transfers preassembled glycans onto nascent proteins in the endoplasmic reticulum. Proper OST function is therefore essential for the glycosylation of many secreted and membrane proteins.
Functional testing showed the identified mutation truncates ribophorin I, destabilizing the protein within the OST complex and causing a specific loss of function in one OST subtype, OST-A. This structural deficit reduced glycan attachment to target proteins normally glycosylated by OST-A, producing the biochemical signature seen in other CDGs. Those glycosylation test patterns provided strong evidence that the family’s disorder represents a novel CDG, now called RPN1-CDG.
According to Hudson Freeze, PhD, director of the Sanford Children’s Health Research Center at Sanford Burnham Prebys, “The glycosylation results from these tests reflected patterns we know well from other CDGs. After confirming that this was a new CDG, the next step was to better understand why it was occurring.” The team’s biochemical and molecular analyses clarified how the truncated ribophorin I impairs OST complex assembly and function.
Defining RPN1-CDG expands the list of OST-related CDG genes to eight and strengthens diagnostic capacity for rare neurodevelopmental disorders. Identifying the molecular mechanism also points researchers toward potential therapeutic strategies. While there is not yet a cure, a precise diagnosis permits targeted research into interventions such as metabolic approaches or genetic therapies that could compensate for the specific OST-A defect.
Funding: The study received support from the National Institutes of Health, the National Institute of Neurological Disorders and Stroke, The Rocket Fund and the Howard Hughes Medical Institute.
Key Questions Answered:
A: Glycans act like quality-control tags that support correct protein folding and stability. The brain depends on a precise network of proteins to form neural circuits. When glycosylation fails, many proteins essential for neural development malfunction, so neurodevelopment is particularly vulnerable.
A: RPN1-CDG is extremely rare. It was identified in a single family in which two siblings were affected, and the exact variant had not been cataloged previously in major genetic databases. With the gene now reported, clinicians can screen other undiagnosed patients for the same mutation.
A: There is no established cure at this time. The diagnostic breakthrough is a critical first step that enables researchers to target the specific biochemical defect—OST-A dysfunction—and to pursue therapeutic strategies such as metabolic treatments or gene-based approaches designed to bypass or correct the underlying molecular problem.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The journal paper was reviewed in full by the editorial team.
- Additional context was added by staff to clarify the findings and their implications.
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 et al., Human Genetics and Genomics Advances.
DOI: 10.1016/j.xhgg.2026.100604