Exome sequencing to identify de novo mutations in sporadic ALS trios

Alessandra Chesi, Stanford University
Brett T. Staahl, Stanford University
Ana Jovicic, Stanford University
Julien Couthouis, Stanford University
Maria Fasolino, University of Pennsylvania
Alya R. Raphael, Stanford University
Tomohiro Yamazaki, Harvard Medical School
Laura Elias, Stanford University
Meraida Polak, Emory University
Crystal Kelly, Emory University
Kelly L. Williams, ANZAC Research Institute
Jennifer A. Fifita, ANZAC Research Institute
Nicholas J. Maragakis, Johns Hopkins University
Garth A. Nicholson, ANZAC Research Institute
Oliver D. King, University of Massachusetts Medical School
Robin Reed, Harvard Medical School
Gerald R. Crabtree, Stanford University
Ian P. Blair, ANZAC Research Institute
Jonathan D. Glass, Emory University
Aaron D. Gitler, Stanford University


Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease whose causes are still poorly understood. To identify additional genetic risk factors, we assessed the role of de novo mutations in ALS by sequencing the exomes of 47 ALS patients and both of their unaffected parents (n = 141 exomes). We found that amino acid-altering de novo mutations were enriched in genes encoding chromatin regulators, including the neuronal chromatin remodeling complex (nBAF) component SS18L1 (also known as CREST). CREST mutations inhibited activity-dependent neurite outgrowth in primary neurons, and CREST associated with the ALS protein FUS. These findings expand our understanding of the ALS genetic landscape and provide a resource for future studies into the pathogenic mechanisms contributing to sporadic ALS.