Somatic mosaicism in amyotrophic lateral sclerosis and frontotemporal dementia identifies focal mutations associated with widespread degeneration
Preprint
Abstract
Although mutations in many genes cause familial amyotrophic lateral sclerosis and frontotemporal dementia, most cases are sporadic (sALS and sFTD) with unclear etiology. We tested whether somatic mutations contribute to sALS and sFTD by deep targeted sequencing of 88 neurodegeneration-related genes in postmortem brain and spinal cord samples from 399 sporadic cases and 144 controls. Predicted deleterious somatic variants in ALS/FTD genes were observed in 2.1% of sporadic cases lacking deleterious germline variants. These variants occurred at very low allele fractions (typically DYNC1H1 and LMNA , genes associated with pediatric motor neuron degeneration. Targeted long-read sequencing further identified one sFTD case with de novo somatic C9orf72 repeat expansions. Together, these findings suggest that rare, focal somatic variants can contribute to sALS and sFTD and drive widespread neurodegeneration.Keywords
Funding Information
- National Institute on Aging (R01 NS032457)
- National Institute on Aging (R56 AG079857)
- National Institute on Aging (R01 AG070921)
- National Institute on Aging (R01 AG088082)
- National Institute on Aging (K08 AG065502)
- National Institute on Aging (K01 AG051791)
- National Institute on Aging (DP2 AG072437)
- National Institute on Aging (R01 AG070921)
- Massachusetts Alzheimer’s Disease Research Center pilot grant
- the Allen Discovery Center program, a Paul G. Allen Frontiers Group advised program of the Paul G. Allen Family Foundation
- the Edward R. and Anne G. Lefler Center postdoctoral fellowship
- National Research Foundation of Korea (RS-2023-00217881)
- National Research Foundation of Korea (RS-2025-02215360)
- the Alzheimer's Association research fellowship
- BrightFocus Foundation (A20201292F)
- Doris Duke Charitable Foundation (2021183)
- Suh Kyungbae Foundation
- the Cullen Education and Research Foundation Young Investigator Award from the Healey Center
- the Holloway Postdoctoral Fellowship from the Association for Frontotemporal Degeneration
- Araminta Broch-Healey Endowed Chair in ALS
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