Zinan Zhou, Junho Kim, August Yue Huang, Matthew Nolan, Junseok Park, Ryan Doan, Taehwan Shin, Michael B. Miller, Mingyun Bae, Boxun Zhao, Jinhyeong Kim, Brian Chhouk, Katherine Morillo, Rebecca C. Yeh, Connor Kenny, Jennifer E. Neil, Chao-Zong Lee, Takuya Ohkubo, John Ravits, Olaf Ansorge, Lyle W. Ostrow, Clotilde Lagier‐Tourenne, Eunjung Alice Lee, Christopher A. Walsh
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.