Scientists at Boston Children’s Hospital and Harvard Medical School have uncovered evidence that rare, localized genetic mutations may spark the onset of devastating brain diseases even when those mutations are present in only a tiny fraction of cells.
The Nature Genetics study, which focused on amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), discovered that these conditions can start with somatic “mosaic” mutations that spread throughout the nervous system.
Despite the association of a handful of genes with these neurodegenerative diseases, 90–95% of cases arise sporadically, without a family history, leaving their origins unclear. Researchers genomically examined 1,787 postmortem tissue samples of various brain regions and spinal cords from hundreds of patients (144 control, 291 ALS, and 117 FTD) who died before the age of 45 but had no family history. The samples were taken from the NIH NeuroBioBank.
Using molecular inversion probe (MIP)-panel sequencing of 88 neurodegeneration-associated genes, they discovered that about 2.1% of sporadic cases carried damaging somatic mutations in one of these disease-related genes. These mutations were extremely rare within the tissue, often present in less than 2% of cells. What makes the discovery noteworthy is where those mutations appear: rather than being distributed throughout the brain, they were concentrated in disease-affected areas, such as the motor cortex and spinal cord in ALS. This pattern suggests that neurodegeneration may begin in a small cluster of genetically altered cells before spreading outward. That idea aligns with existing theories that ALS and FTD progression involve the movement of toxic proteins, particularly TDP-43, between cells in a prion-like manner. A single focal mutation could initiate this cascade, effectively “seeding” disease.
Senior author Christopher A. Walsh, MD, PhD, Howard Hughes Medical Institute investigator and professor at BCH and HMS, told Inside Precision Medicine, “Above all, it suggests that the genes, or at least some of the genes, that drive the disease don’t necessarily have their toxic effects only in the neurons carrying the mutation. Or that some neurons are impacted and that leads to a domino effect that somehow impacts neurons that don’t carry the mutation.”
The study also identified mutations in unexpected genes, including DYNC1H1 and LMNA, which are typically linked to severe childhood neurological disorders. Inherited versions of these mutations are often incompatible with long-term survival, but when present only in a subset of brain cells, they may allow normal early development followed by late-onset neurodegeneration. In another key finding, researchers detected spontaneous expansions in the C9orf72 gene—the most common genetic cause of inherited ALS and FTD—arising directly within brain tissue. This provides some of the first evidence that such disease-causing expansions can occur somatically rather than being inherited.
Together, the results point to a new model of disease: ALS and FTD may not always begin with widespread genetic risk but instead with rare, localized mutations that trigger broader neurodegeneration over time. The discovery also highlights a major challenge for diagnosis. Because these mutations can be confined to the brain and present at extremely low levels, they would likely be missed by standard genetic tests using blood or saliva.
According to Walsh, the results highlight the importance of creating a more sophisticated clinical strategy. “Clinically translating these findings immediately is a challenge, because most of the variants we find are likely limited to the brain and hence unavailable to clinical sequencing,” said Walsh.
The researchers believe that these findings pave the way for novel methods, both for identifying concealed genetic alterations in the brain and for creating treatments that target early, localized disease processes before they proliferate.
Walsh said, “If we see that gene-directed anti-sense oligonucleotide (ASO) therapies (like the ongoing FUS trial) are incompletely effective, it could reflect that the degeneration is a widespread process. Or it may suggest the importance of starting these ASO trials at the earliest possible stage to try to block secondary processes.”
While the proportion of cases explained by these mutations is still small, the work underscores a growing realization in neuroscience: even a handful of altered cells may be enough to set off widespread brain disease.
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