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

Uniformed Services University of the Health Sciences

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

66 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
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 - 3 Feb 2021

Keywords

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

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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

@article{cb4cfd7a57c14cb18f65c142c631d39e,

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 Lewis, {Elizabeth A.} and Andrew King and Daniela Calini and Viviana Pensato and Dalgard, {Clifton L.}",

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

year = "2021",

month = feb,

day = "3",

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

language = "English",

volume = "109",

pages = "448--460.e4",

journal = "Neuron",

issn = "0896-6273",

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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

TY - JOUR

T1 - Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis

AU - The PROSPECT Consortium

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 - 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 - Dalgard, Clifton L.

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

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U2 - 10.1016/j.neuron.2020.11.005

DO - 10.1016/j.neuron.2020.11.005

M3 - Article

AN - SCOPUS:85097045939

SN - 0896-6273

VL - 109

SP - 448-460.e4

JO - Neuron

JF - Neuron

IS - 3

ER -

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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Keywords

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