Summary: Frontotemporal dementia (FTD) is a debilitating neurodegenerative disorder that often appears in midlife, disrupting behavior, personality and language well before memory loss becomes prominent. A rare and puzzling subtype, atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions (aFTLD-U), has long been labeled “sporadic” because it typically occurs without a clear family history. New research from VIB and the University of Antwerp identifies a major genetic risk factor for aFTLD-U: a repeat expansion in the GOLGA8A gene. This discovery, present in nearly 60% of confirmed cases, is an unusually strong genetic signal for a disease previously thought to lack a clear genetic basis and provides a concrete biological target for diagnosis and therapeutic development.
Key facts
- GOLGA8A repeat expansion: Long-read sequencing revealed a tandem repeat expansion in an intron of GOLGA8A that is strongly associated with aFTLD-U.
- Strong genetic signal: The association is pronounced — far stronger than typically seen for so-called sporadic disorders — and is present in the majority of studied aFTLD-U patients.
- Young onset and misdiagnosis: This subtype usually presents in patients’ 30s or 40s, with behavioral and personality changes that are frequently misattributed to stress or psychiatric conditions.
- Diagnostic potential: The genetic marker offers the first realistic route to diagnosing aFTLD-U in living patients instead of relying solely on autopsy confirmation.
Researchers at VIB and the University of Antwerp report their findings in Nature Genetics. The study combines a focused genome-wide association study (GWAS) with state-of-the-art long-read sequencing, enabling the team to find and characterize a small but consequential DNA repeat that had been invisible to standard approaches. The work opens a biological entry point for a subtype of FTD that was previously hard to study and even harder to identify in life.
FTD affects regions of the brain that control social behavior, decision-making and language. Early signs typically involve personality change, loss of empathy, disinhibition or language problems—symptoms that can devastate careers and relationships because they often appear when people are still professionally active. Prof. Rosa Rademakers (VIB-UAntwerp Center for Molecular Neurology) and colleagues have focused on the genetics of FTD subtypes and pursued this rare aFTLD-U subtype despite its sporadic presentation.
A global gene hunt
Because aFTLD-U is rare, assembling a sufficiently large and well-characterized cohort required extensive international collaboration. The team first performed a GWAS on 59 pathologically confirmed aFTLD-U cases and over 3,000 controls, which highlighted a locus on chromosome 15q14 with an unusually strong association signal. Integrating additional case data and leveraging long-read sequencing from more than a thousand genomes allowed the researchers to pinpoint a tandem repeat in an intronic region of GOLGA8A. Variations in repeat length and motif composition were observed, with longer CT-dimer expansions particularly enriched in affected individuals.
Long-read sequencing was essential: short-read approaches often cannot resolve complex or highly repetitive regions of the genome, and GOLGA8A belongs to a genomic area with multiple similar copies. The ability to read long stretches of DNA made it possible to both detect and characterize this repeat expansion, a variant that involves a simple two-nucleotide motif repeated many times.
New questions and new hope
The repeat expansion’s functional effects are not yet fully understood, but its frequency in nearly 60% of aFTLD-U cases implies a central role in disease biology. Current research in the lab focuses on how the repeat might alter gene regulation, RNA processing or other cellular pathways in frontal and temporal brain regions vulnerable to degeneration.
Investigators emphasize that this repeat is not the complete explanation for all aFTLD-U cases. Some patients lack the expansion, suggesting there are additional genetic or environmental contributors, perhaps hidden in other difficult-to-sequence genomic regions. The discovery does, however, change the way researchers and clinicians should view “sporadic” disease: even without a family history, a substantial genetic component can exist and be actionable.
Clinical and research implications
Practically, the identification of the GOLGA8A repeat expansion makes a molecular diagnostic test conceivable. In the future, testing for this expansion in blood or DNA samples could enable earlier, subtype-specific diagnoses while patients are still alive, improving clinical care and patient stratification for trials. For research, the finding provides a tractable biological target around which mechanistic studies and therapeutic strategies can be developed.
Frequently asked questions
- Q: How can a disease be genetic without a family history? A: Some genetic variants arise de novo or are present in a form and frequency that does not produce a clear familial pattern. Repeat expansions can expand or behave unpredictably, so a disease can appear “sporadic” yet still have a strong genetic driver.
- Q: Why does FTD affect personality more than memory? A: FTD primarily damages the frontal and temporal lobes, which govern social behavior, judgment and language. Memory centers are affected later or less prominently, which is why personality and behavior changes are often the earliest signs.
- Q: Is there a test now? A: Not yet as a routine clinical test, but the discovery enables development of a diagnostic assay. Detection of the GOLGA8A repeat expansion in DNA could become a confirmatory test for aFTLD-U in living patients.
Editorial notes
- This article was edited by a Neuroscience News editor and informed by the full journal publication.
- Findings are based on an open-access research paper reporting the discovery and analysis of the GOLGA8A repeat expansion in aFTLD-U.
About this research
Author: Gunnar De Winter
Source: VIB
Contact: Gunnar De Winter – VIB
Image credit: Neuroscience News
Original research: “A repeat expansion in GOLGA8A is a major risk factor for atypical frontotemporal lobar degeneration with ubiquitin positive inclusions” (Nature Genetics, DOI: 10.1038/s41588-026-02537-7). The study combines GWAS and long-read genome sequencing to reveal a tandem repeat expansion that likely plays a key role in aFTLD-U pathogenesis and provides a foundation for future diagnostic and therapeutic advances.