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

The PROSPECT Consortium; The American Genome Center (TAGC); The FALS Sequencing Consortium; The Genomics England Research Consortium; The International ALS/FTD Genomics Consortium (iAFGC); The International FTD Genetics Consortium (IFGC); The International LBD Genomics Consortium (iLBDGC), The NYGC ALS Consortium; the University of Maryland Brain and Tissue Bank and NIH NeuroBioBank

doi:10.1016/j.neuron.2020.11.005

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

The PROSPECT Consortium, The American Genome Center (TAGC), The FALS Sequencing Consortium, The Genomics England Research Consortium, The International ALS/FTD Genomics Consortium (iAFGC), The International FTD Genetics Consortium (IFGC), The International LBD Genomics Consortium (iLBDGC), The NYGC ALS Consortium, the University of Maryland Brain and Tissue Bank and NIH NeuroBioBank

Research output: Contribution to journal › Article › peer-review

62 Scopus citations

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 (US)
Pages (from-to)	448-460.e4
Journal	Neuron
Volume	109
Issue number	3
DOIs	https://doi.org/10.1016/j.neuron.2020.11.005
State	Published - Feb 3 2021

Funding

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. 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 ).

Keywords

amyotrophic lateral sclerosis
frontotemporal dementia
huntingtin
repeat expansions
whole-genome sequencing

ASJC Scopus subject areas

General Neuroscience

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10.1016/j.neuron.2020.11.005

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The PROSPECT Consortium, The American Genome Center (TAGC), The FALS Sequencing Consortium, The Genomics England Research Consortium, The International ALS/FTD Genomics Consortium (iAFGC), The International FTD Genetics Consortium (IFGC), The International LBD Genomics Consortium (iLBDGC), The NYGC ALS Consortium, & the University of Maryland Brain and Tissue Bank and NIH NeuroBioBank (2021). Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis. Neuron, 109(3), 448-460.e4. https://doi.org/10.1016/j.neuron.2020.11.005

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title = "Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis",

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.",

keywords = "amyotrophic lateral sclerosis, frontotemporal dementia, huntingtin, repeat expansions, whole-genome sequencing",

author = "{The PROSPECT Consortium} and {The American Genome Center (TAGC)} and {The FALS Sequencing Consortium} and {The Genomics England Research Consortium} and {The International ALS/FTD Genomics Consortium (iAFGC)} and {The International FTD Genetics Consortium (IFGC)} and {The International LBD Genomics Consortium (iLBDGC), The NYGC ALS Consortium} and {the University of Maryland Brain and Tissue Bank and NIH NeuroBioBank} and Ramita Dewan and Ruth Chia and Jinhui Ding and Hickman, {Richard A.} and Stein, {Thor D.} and Yevgeniya Abramzon and Sarah Ahmed and Sabir, {Marya S.} and Portley, {Makayla K.} and Arianna Tucci and Kristina Ib{\'a}{\~n}ez and Shankaracharya, {F. N.U.} and Pamela Keagle and Giacomina Rossi and Paola Caroppo and Fabrizio Tagliavini and Waldo, {Maria L.} and Johansson, {Per M.} and Nilsson, {Christer F.} and Adelani Adeleye and Camille Alba and Dagmar Bacikova and Hupalo, {Daniel N.} and Martinez, {Elisa Mc Grath} and Pollard, {Harvey B.} and Gauthaman Sukumar and Soltis, {Anthony R.} and Meila Tuck and Xijun Zhang and Wilkerson, {Matthew D.} and Smith, {Bradley N.} and Nicola Ticozzi and Claudia Fallini and Gkazi, {Athina Soragia} and Topp, {Simon D.} and Jason Kost and Scotter, {Emma L.} and Kenna, {Kevin P.} and Miller, {Jack W.} and Cinzia Tiloca and Caroline Vance and Danielson, {Eric W.} and Claire Troakes and Claudia Colombrita and Safa Al-Sarraj and Erik Pioro and Bigio, {Eileen H.} and Flanagan, {Margaret E.} and Qinwen Mao and Mesulam, {Marek Marsel}",

note = "Publisher Copyright: {\textcopyright} 2020",

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day = "3",

doi = "10.1016/j.neuron.2020.11.005",

language = "English (US)",

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The PROSPECT Consortium, The American Genome Center (TAGC), The FALS Sequencing Consortium, The Genomics England Research Consortium, The International ALS/FTD Genomics Consortium (iAFGC), The International FTD Genetics Consortium (IFGC), The International LBD Genomics Consortium (iLBDGC), The NYGC ALS Consortium & the University of Maryland Brain and Tissue Bank and NIH NeuroBioBank 2021, 'Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis', Neuron, vol. 109, no. 3, pp. 448-460.e4. https://doi.org/10.1016/j.neuron.2020.11.005

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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 - Pioro, Erik

AU - Bigio, Eileen H.

AU - Flanagan, Margaret E.

AU - Mao, Qinwen

AU - Mesulam, Marek Marsel

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.

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KW - frontotemporal dementia

KW - huntingtin

KW - repeat expansions

KW - whole-genome sequencing

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The PROSPECT Consortium, The American Genome Center (TAGC), The FALS Sequencing Consortium, The Genomics England Research Consortium, The International ALS/FTD Genomics Consortium (iAFGC), The International FTD Genetics Consortium (IFGC) et al. Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis. Neuron. 2021 Feb 3;109(3):448-460.e4. doi: 10.1016/j.neuron.2020.11.005

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

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