Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis

• DOI: 10.2139/ssrn.3652331
• Publication Date: 2020-08-12T12:17:38Z
• Authors: Ramita Dewan; Ruth Chia; Jinhui Ding; Richard Hickman; Thor Stein; Yevgeniya Abramzon; Sarah Ahmed; Marya S. Sabir; Makayla K. Portley; Arianna Tucci; Kristina Ibáñez; Pamela Keagle; Giacomina Rossi; Paola Caroppo; Fabrizio Tagliavini; Maria L. Waldo; Per M. Johansson; Christer F. Nilsson; The American Geno...; The FALS Sequenci...; The Genomics Engl...; The International...; The International...; The International...; The NYGC ALS Cons...; The PROSPECT Cons...; James Rowe; Luisa Benussi; Giuliano Binetti; Roberta Ghidoni; Edwin Jabbari; Coralie Viollet; Jonathan D. Glass; Andrew B. Singleton; Vincenzo Silani; Owen A. Ross; Mina Ryten; Ali Torkamani; Tanaka Toshiko; Luigi Ferrucci; Susan M. Resnick; Stuart Pickering-...; Christopher B. Brady; Neil Kowal; John A. Hardy; Vivianna Van Deerlin; Jean Paul Vonsattel; Matthew B. Harms; Huw R. Morris; Raffaele Ferrari; John E. Landers; Adriano Chiò; J. Raphael Gibbs; Clifton L. Dalgard; Sonja Scholz; Bryan J. Traynor
• Keywords: C9ORF72

To examine the role of repeat expansions in pathogenesis frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), we performed sizing ten genetic loci previously implicated neurodegenerative diseases. We examined whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body (LBD) 3,158 neurologically healthy subjects. Pathogenic (range: 40 to 64 CAG repeats) huntingtin (HTT) gene were found three (0.12%) patients diagnosed with pure syndromes but not present LBD or cohorts. replicated our findings an independent cohort, identified five (0.14%) out 3,674 harboring pathogenic HTT expansions. Postmortem evaluations two revealed huntingtin-positive, as well TDP43- ubiquitin-positive aggregates, predominantly frontal cortex, without neostriatal atrophy. Our reveal etiological relationship between syndromes, indicate that screening for should be considered.