Clotilde Lagier-Tourenne, MD, PhD

While known genetic mutations for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) can be passed down through families, the vast majority (90–95%) of ALS and FTD cases occur without a clear inherited cause. So what’s prompting these sporadic cases?

This was the guiding question of a recent study out of Mass General Brigham and Boston Children’s Hospital, co-led by Zinan Zhou, PhD, Junho Kim, PhD, and August Yue Huang, PhD, and jointly supervised by Clotilde Lagier-Tourenne, MD, PhD, Eunjung Alice Lee, PhD, and Christopher Walsh, MD, PhD.

The team examined postmortem brain and spinal cord samples from hundreds of people with sporadic ALS or FTD, along with matched controls, to determine whether somatic mutations—genetic changes that arise during life—might play a role. They performed ultra-deep sequencing of a panel of 88 neurodegeneration-associated genes to search for rare somatic mutations.

In about 2% of sporadic cases, they identified potentially harmful mutations that appeared in only a small fraction of cells and were often confined to disease-affected regions of the brain and spinal cord. The researchers also found evidence that somatic mutations in two genes linked to severe childhood motor neuron disease may contribute to some sporadic cases.

Finally, they showed that hallmark ALS/FTD mutations, such as the C9orf72 repeat expansion, can arise somatically (within the body) during a person’s lifetime.

Overall, the findings suggest that rare, localized somatic mutations may lead to sporadic ALS and FTD and later drive widespread neurodegeneration, underscoring the need to rethink how genetic risk is assessed in these diseases.

Published in Nature Genetics on April 15, 2026 | Read the paper: “Somatic mosaicism in ALS and FTD identifies focal mutations associated with widespread degeneration”

Summary reviewed by: Clotilde Lagier-Tourenne, MD, PhD, co-lead author