Abstract
“Oligogenic inheritance” is used to describe cases where more than one rare pathogenic variant is observed in the same individual. While multiple variants can alter disease presentation, the necessity of multiple variants to instigate pathogenesis has not been addressed in amyotrophic lateral sclerosis (ALS). We sequenced ALS-associated genes in C9orf72-expansion-positive and negative ALS patients, alongside unaffected controls, to test the importance of oligogenicity and variant deleteriousness in ALS. We found that all groups had similar numbers of rare variants, but that variant severity was significantly higher in C9orf72-negative ALS cases, suggesting sufficiency of C9orf72 expansion to cause ALS alone.
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Acknowledgments
We would like to thank the participants of the study. We thank Michael Strong and Angela Genge for sample contribution. We thank Vessela Zaharieva and Cathy Mirarchi for their assistance in clinical coordination. We thank Cynthia Bourassa, Fulya Akçimen, Qin He, and Cal Liao for their assistance.
Funding
Jay Ross has received a doctoral student fellowship from the ALS Society of Canada and a Canadian Institutes of Health Research Frederick Banting & Charles Best Canada Graduate Scholarship (FRN 159279). We thank the ALS Society of Canada, the Canadian Institutes of Health Research, and Brain Canada for research funding.
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JPR: Experimental design, experimental procedures, data analysis, statistical analysis, writing manuscript, editing manuscript.
CSL: Experimental design, experimental procedures, editing manuscript.
SBL: Experimental procedures.
DS: Data analysis.
ADL: Data analysis.
WC: Collection of genetic samples, editing manuscript.
ND: Collection of genetic samples, editing manuscript.
PAD: Experimental design, writing manuscript, editing manuscript.
GAR: Experimental design, collection of genetic samples, writing manuscript, editing manuscript.
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Ross, J.P., Leblond, C.S., Laurent, S.B. et al. Oligogenicity, C9orf72 expansion, and variant severity in ALS. Neurogenetics 21, 227–242 (2020). https://doi.org/10.1007/s10048-020-00612-7
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DOI: https://doi.org/10.1007/s10048-020-00612-7