Somatic mosaicism in ALS and FTD identifies focal mutations associated with widespread degeneration
Although mutations in many genes cause familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), most cases are sporadic (sALS and sFTD) with unclear etiology. Here 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 <2%) and were often focal and enriched in disease-affected regions. Analysis of bulk RNA-sequencing data from an additional cohort identified deleterious somatic variants in 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.
Authors
- Mingyun Bae (ORCID: https://orcid.org/0009-0000-8144-476X)
- Michael B. Miller (ORCID: https://orcid.org/0000-0002-6205-3314)
- Taehwan Shin (ORCID: https://orcid.org/0000-0003-3604-8594)
- Takuya Ohkubo
- Lyle W. Ostrow (ORCID: https://orcid.org/0000-0001-7158-5243)
- August Yue Huang (ORCID: https://orcid.org/0000-0002-0416-2854)
- Eunjung Alice Lee (ORCID: https://orcid.org/0000-0002-6574-9261)
- Junho Kim (ORCID: https://orcid.org/0000-0003-3513-401X)
- Connor Kenny (ORCID: https://orcid.org/0000-0001-6328-8935)
- Clotilde Lagier‐Tourenne (ORCID: https://orcid.org/0000-0002-3058-8322)
- Rebecca C. Yeh
- Olaf Ansorge (ORCID: https://orcid.org/0000-0003-1825-5434)
- Boxun Zhao (ORCID: https://orcid.org/0000-0003-2337-5756)
- Jennifer E. Neil
- Zinan Zhou
- Brian Chhouk
- Ryan Doan
- John Ravits
- Jinhyeong Kim (ORCID: https://orcid.org/0009-0002-0466-3023)
- Katherine Morillo
- Junseok Park
- Christopher A. Walsh (ORCID: https://orcid.org/0000-0002-0156-2238)
- Chao-Zong Lee
Institutions
- Brigham and Women's Hospital (US)
- Boston Children's Hospital (US)
- Howard Hughes Medical Institute (US)
- Harvard University (US)
- University of California San Diego (US)
- University of Oxford (GB)
- Massachusetts General Hospital (US)
- Yokohama Municipal Minato Red Cross Hospital (JP)
- Boston Children's Museum (US)
- Temple University (US)
- Sungkyunkwan University (KR)
Publication Details
- Journal
- Nature Genetics
- Published
- 2026-04-15
- DOI
- https://doi.org/10.1038/s41588-026-02570-6
- Primary Topic
- Amyotrophic Lateral Sclerosis Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00