Abstract
We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing 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, 40–64 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 collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington's disease was absent in both cases. 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.
| Original language | English |
|---|---|
| Pages (from-to) | 448-460.e4 |
| Journal | Neuron |
| Volume | 109 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 3 Feb 2021 |
Keywords
- amyotrophic lateral sclerosis
- frontotemporal dementia
- huntingtin
- repeat expansions
- whole-genome sequencing
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In: Neuron, Vol. 109, No. 3, 03.02.2021, p. 448-460.e4.
Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis
AU - Dewan, Ramita
AU - Chia, Ruth
AU - Ding, Jinhui
AU - Hickman, Richard A.
AU - Stein, Thor D.
AU - Abramzon, Yevgeniya
AU - Ahmed, Sarah
AU - Sabir, Marya S.
AU - Portley, Makayla K.
AU - Tucci, Arianna
AU - Ibáñez, Kristina
AU - Shankaracharya, F. N.U.
AU - Keagle, Pamela
AU - Rossi, Giacomina
AU - Caroppo, Paola
AU - Tagliavini, Fabrizio
AU - Waldo, Maria L.
AU - Johansson, Per M.
AU - Nilsson, Christer F.
AU - Adeleye, Adelani
AU - Alba, Camille
AU - Bacikova, Dagmar
AU - Hupalo, Daniel N.
AU - Martinez, Elisa Mc Grath
AU - Pollard, Harvey B.
AU - Sukumar, Gauthaman
AU - Soltis, Anthony R.
AU - Tuck, Meila
AU - Zhang, Xijun
AU - Wilkerson, Matthew D.
AU - Smith, Bradley N.
AU - Ticozzi, Nicola
AU - Fallini, Claudia
AU - Gkazi, Athina Soragia
AU - Topp, Simon D.
AU - Kost, Jason
AU - Scotter, Emma L.
AU - Kenna, Kevin P.
AU - Miller, Jack W.
AU - Tiloca, Cinzia
AU - Vance, Caroline
AU - Danielson, Eric W.
AU - Troakes, Claire
AU - Colombrita, Claudia
AU - Al-Sarraj, Safa
AU - Lewis, Elizabeth A.
AU - King, Andrew
AU - Calini, Daniela
AU - Pensato, Viviana
AU - Krüger, Rejko
AU - The American Genome Center (TAGC)
AU - The FALS Sequencing Consortium
AU - The Genomics England Research Consortium
AU - The International ALS/FTD Genomics Consortium (iAFGC)
AU - The International FTD Genetics Consortium (IFGC)
AU - The International LBD Genomics Consortium (iLBDGC), The NYGC ALS Consortium
AU - the University of Maryland Brain and Tissue Bank and NIH NeuroBioBank
AU - The PROSPECT Consortium
N1 - Funding Information: We thank contributors who collected samples used in this initiative and the patients and families, whose help and participation made this work possible. This research was supported by the Intramural Research Program of the National Institutes of Health (National Institute on Aging, National Institute of Neurological Disorders and Stroke, project numbers 1ZIAAG000935 [Principal Investigator (PI) Bryan J. Traynor], 1ZIANS003154 [PI Sonja W. Scholz], and 1ZIANS0030033 and 1ZIANS003034 [David S. Goldstein]). Drs. Sidransky, Grisel Lopez, and Tayebi were supported by the Intramural Research Program of the National Human Genome Research Institute. This research was supported by the Italian Ministry of Health (Ricerca Corrente). R.A.H. is a Columbia University Irving Medical Center ADRC Research Education Component trainee (P30 AG066462-01, PI Scott Small) and is supported by grants from the Hereditary Disease Foundation and Huntington Disease Society of America. J.B.R. is supported by the Wellcome Trust (103838) and National Institute for Health Research Cambridge Biomedical Research Centre. J.E.L. was supported by the National Institutes of Health/National Institute of Neurological Disorders (R01NS073873). The American Genome Center is supported by NHLBI grant IAA-A-HL-007.001. The sequencing activities at NYGC were supported by the ALS Association (grant 19-SI-459) and the Tow Foundation. This study used the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD (https://hpc.nih.gov). L.B. G.B. C.B.B. P.C. A.C. R.F. L.F. R.G. J.D.G. J.A.H. M.B.H. R.A.H. K.I. E.J. P.M.J. N.K. J.E.L. H.R.M. C.F.N. S.P.-B. S.M.R. O.A.R. G.R. J.B.R. M.R. S.W.S. V.S. A.B.S. T.D.S. F.T. T.T. A. Torkamani, B.J.T. V.V. J.P.V. and M.L.W. collected and prepared the samples and performed the clinical evaluations. Y.A. S.A. R.C. A.C. C.L.D. R.D. J.D. R.F. J.G. M.B.H. R.A.H. P.K. J.E.L. H.R.M. M.K.P. M.S.S. T.D.S. A. Tucci, V.V. C.V. J.P.V. and S. conducted the experiments and the data analysis. R.D. S.W.S. and B.J.T. wrote the manuscript. A.C. R.F. L.F. J.G. J.A.H. M.B.H. J.E.L. H.R.M. A.B.S. S.W.S. and B.J.T. designed and supervised the experiments. S.P.-B. A.B.S. J.A.H. H.R.M. and B.J.T. hold US, EU, and Canadian patents on the clinical testing and therapeutic intervention for the hexanucleotide repeat expansion of C9 or f72. S.W.S. serves on the scientific advisory council of the Lewy Body Dementia Association and is an editorial board member for the Journal of Parkinson's Disease. B.J.T. is an editorial board member for JAMA Neurology, JNNP, and Neurobiology of Aging. V.S. is on the journal editorial boards of Amyotrophic Lateral Sclerosis, European Neurology, American Journal of Neurodegenerative Diseases, and Frontiers in Neurology. He has also received compensation for consulting services and speaking activities from AveXis, Cytokinetics, Italfarmaco, and Zambon. J.B.R. is an editor for Brain and has received compensation for consulting services from Asceneuron, Biogen, UCB, Astex, and SV Health. J.E.L. is a member of the scientific advisory board for Cerevel Therapeutics and a consultant and provides expert testimony for Perkins Coie. Funding Information: We thank contributors who collected samples used in this initiative and the patients and families, whose help and participation made this work possible. This research was supported by the Intramural Research Program of the National Institutes of Health ( National Institute on Aging , National Institute of Neurological Disorders and Stroke , project numbers 1ZIAAG000935 [Principal Investigator (PI) Bryan J. Traynor], 1ZIANS003154 [PI Sonja W. Scholz], and 1ZIANS0030033 and 1ZIANS003034 [David S. Goldstein]). Drs. Sidransky, Grisel Lopez, and Tayebi were supported by the Intramural Research Program of the National Human Genome Research Institute . This research was supported by the Italian Ministry of Health (Ricerca Corrente). R.A.H. is a Columbia University Irving Medical Center ADRC Research Education Component trainee ( P30 AG066462-01 , PI Scott Small) and is supported by grants from the Hereditary Disease Foundation and Huntington Disease Society of America . J.B.R. is supported by the Wellcome Trust ( 103838 ) and National Institute for Health Research Cambridge Biomedical Research Centre . J.E.L. was supported by the National Institutes of Health /National Institute of Neurological Disorders (R01NS073873). The American Genome Center is supported by NHLBI grant IAA-A-HL-007.001 . The sequencing activities at NYGC were supported by the ALS Association (grant 19-SI-459 ) and the Tow Foundation . This study used the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health , Bethesda, MD ( https://hpc.nih.gov ). Publisher Copyright: © 2020
PY - 2021/2/3
Y1 - 2021/2/3
N2 - We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing 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, 40–64 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 collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington's disease was absent in both cases. 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.
AB - We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing 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, 40–64 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 collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington's disease was absent in both cases. 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.
KW - amyotrophic lateral sclerosis
KW - frontotemporal dementia
KW - huntingtin
KW - repeat expansions
KW - whole-genome sequencing
UR - http://www.scopus.com/inward/record.url?scp=85097045939&partnerID=8YFLogxK
UR - https://pubmed.ncbi.nlm.nih.gov/33242422
U2 - 10.1016/j.neuron.2020.11.005
DO - 10.1016/j.neuron.2020.11.005
M3 - Article
C2 - 33242422
AN - SCOPUS:85097045939
SN - 0896-6273
VL - 109
SP - 448-460.e4
JO - Neuron
JF - Neuron
IS - 3
ER -