A global team of scientists has uncovered a new genetic risk factor for a rare and aggressive form of early-onset frontotemporal dementia, according to a study published in Nature Genetics.
The findings reveal new details about a disease that has long defied explanation, highlighting the growing importance of advanced genome sequencing technologies, said Rudolph Castellani, MD, professor of Pathology, a co-author of the study.
“This is a multi-institutional study that leveraged expertise and case material from numerous academic centers throughout the U.S., Canada, Europe and Australia,” said Castellani, who directs the Division of Neuropathology at Feinberg.
In the study, Castellani and collaborators set out to better understand atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions (aFTLD-U), a rare subtype of an already rare frontotemporal dementia that typically affects people at a young age and progresses rapidly.
Until now, the condition has been defined primarily by its unique brain pathology — abnormal aggregation of proteins — rather than by a clear underlying genetic cause.
Using a genome-wide association study of 59 individuals with aFTLD-U and more than 3,100 control subjects, the investigators identified a risk locus, or location, on chromosome 15. This genetic variant increased the odds of developing the disease more than 26-fold — an exceptionally strong effect in the context of neurodegenerative disorders, where most genetic risk factors only slightly increase susceptibility, Castellani said.
“The main finding is that of a novel genetic alteration which requires ‘long-read genomic sequencing’ to identify — this type of sequencing allows interrogation of non-coding segments of DNA,” Castellani said.
By leveraging long-read sequencing data and analyzing DNA structures often invisible to conventional methods, the scientists identified an expanded DNA repeat within the gene GOLGA8A. This anomaly was present in nearly 60 percent of aFTLD-U cases, establishing it as the most common known risk factor for the condition.
“The genetic alteration is a repeat expansion of an intronic segment of DNA, meaning that the disease could be driven by a segment of DNA that is largely dormant, or unutilized for normal biological processes,” Castellani said.
Unlike many well-known disease-causing mutations, the newly identified variant does not affect the protein-coding portion of the gene. Instead, it lies in a stretch of DNA once considered “junk.” The discovery raises new questions about how non-coding regions influence brain health.
Although the impact of the GOLGA8A variant remains unclear, its presence in aFTLD-U — and its absence in most other neurodegenerative diseases —suggests it plays a central role in driving the disorder, Castellani said.
Moving forward, Castellani and his research group will continue to study the genetic variant, its impact on brain health, and attempt to identify potential therapeutic targets, he said.
The study also underscores how rare-disease research increasingly depends on international cooperation, both to collect enough cases to study and to combine specialized expertise.
“Such studies are only possible through an extensive collaborative effort across the entire planet and underscore the importance of research efforts at individual institutions,” said Castellani, who is a member of the Mesulam Institute for Cognitive Neurology and Alzheimer’s Disease. “Northwestern has particular expertise in this group of disorders, so it makes sense that we were called upon to support the effort.”
The study was partly funded by the Flanders Institute for Biotechnology, Belgium, the University of Antwerp and the National Institutes of Health under grants: P30AG013854, R01AG77444, P30AG062677, P30AG062429, P30AG066468, P01AG066597, P30AG072979, P30AG072976, P30AG062422, R01AG062566, R01AG037491, P01AG019724, P30AG066511, U01AG057195, U19AG063911, P30AG066444, K08AG065463, R01AG089380, R01AG087165 and P30AG072972.
