Boston University - Chronic Traumatic Encephalopathy Center; Department of Veterans Affairs (VA); Boston University - Alzheimer's Disease Center; Boston University - Department of Pathology and Laboratory Medicine
Government of the United States of America - Center for Alzheimer's and Related Dementias (CARD); National Institute on Aging (NIA) - Molecular Genetics Section
To examine the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), we performed repeat sizing of ten genetic loci previously implicated in neurodegenerative diseases. We examined whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range: 40 to 64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent cohort, and identified five (0.14%) out of 3,674 FTD/ALS patients harboring pathogenic HTT CAG expansions. Postmortem evaluations of two patients revealed huntingtin-positive, as well as TDP43- and ubiquitin-positive aggregates, predominantly in the frontal cortex, without neostriatal atrophy. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes, and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.
Dewan, Ramita and Chia, Ruth and Ding, Jinhui and Hickman, Richard and Stein, Thor and Abramzon, Yevgeniya and Ahmed, Sarah and Sabir, Marya S. and Portley, Makayla K. and Tucci, Arianna and Ibáñez, Kristina and , Shankaracharya and Keagle, Pamela and Rossi, Giacomina and Caroppo, Paola and Tagliavini, Fabrizio and Waldo, Maria L. and Johansson, Per M. and Nilsson, Christer F. and Center (TAGC), The American Genome and Consortium, The FALS Sequencing and Consortium, The Genomics England Research and Consortium (iAFGC), The International ALS/FTD Genomics and Consortium (IFGC), The International FTD Genetics and Consortium (iLBDGC), The International LBD Genomics and Consortium, The NYGC ALS and Consortium, The PROSPECT and Rowe, James and Benussi, Luisa and Binetti, Giuliano and Ghidoni, Roberta and Jabbari, Edwin and Viollet, Coralie and Glass, Jonathan D. and Singleton, Andrew B. and Silani, Vincenzo and Ross, Owen A. and Ryten, Mina and Torkamani, Ali and Tanaka, Toshiko and Ferrucci, Luigi and Resnick, Susan M. and Pickering-Brown, Stuart and Brady, Christopher B. and Kowal, Neil and Hardy, John A. and Deerlin, Vivianna Van and Vonsattel, Jean Paul and Harms, Matthew B. and Morris, Huw R. and Ferrari, Raffaele and Landers, John E. and Chiò, Adriano and Gibbs, J. Raphael and Dalgard, Clifton L. and Scholz, Sonja and Traynor, Bryan J., Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis. Available at SSRN: https://ssrn.com/abstract=3652331 or http://dx.doi.org/10.2139/ssrn.3652331
This version of the paper has not been formally peer reviewed.
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