Pathogenic huntingtin repeat expansions in patients with frontotemporal dementia and amyotrophic lateral sclerosis

Ramita Dewan; Ruth Chia; Jinhui Ding; Richard A. Hickman; Sarah Ahmed; Marya S. Sabir; Makayla K. Portley; Arianna Tucci; Kristina Ibáñez; F. N. U. Shankaracharya; Pamela Keagle; Giacomina Rossi; Paola Caroppo; Fabrizio Tagliavini; Maria L. Waldo; Per M. Johansson; Christer F. Nilsson; 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 PROSPECT Consortium; James B. 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; Toshiko Tanaka; Luigi Ferrucci; Susan M. Resnick; Stuart Pickering-Brown; 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 W. Scholz; Bryan J. Traynor

doi:10.1016/j.neuron.2020.11.005

Pathogenic huntingtin repeat expansions in patients with frontotemporal dementia and amyotrophic lateral sclerosis

Ramita Dewan, Ruth Chia, Jinhui Ding, Richard A. Hickman, Sarah Ahmed, Marya S. Sabir, Makayla K. Portley, Arianna Tucci, Kristina Ibáñez, F. N. U. Shankaracharya, Pamela Keagle, Giacomina Rossi, Paola Caroppo, Fabrizio Tagliavini, Maria L. Waldo, Per M. Johansson, Christer F. Nilsson, The American Genome Center (TAGC), The FALS Sequencing Consortium, The Genomics England Research ConsortiumThe International ALS/FTD Genomics Consortium (iAFGC), The International FTD Genetics Consortium (IFGC), The International LBD Genomics Consortium (iLBDGC), The NYGC ALS Consortium, The PROSPECT Consortium, James B. 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, Toshiko Tanaka, Luigi Ferrucci, Susan M. Resnick, Stuart Pickering-Brown, 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 W. Scholz, Bryan J. Traynor^*

^*Corresponding author for this work

Faculty of Medicine, Health and Human Sciences

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

70 Citations (Scopus)

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
Number of pages	18
Journal	Neuron
Volume	109
Issue number	3
Early online date	26 Nov 2020
DOIs	https://doi.org/10.1016/j.neuron.2020.11.005
Publication status	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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Dewan, R., Chia, R., Ding, J., Hickman, R. A., Ahmed, S., Sabir, M. S., Portley, M. K., Tucci, A., Ibáñez, K., Shankaracharya, F. N. U., Keagle, P., Rossi, G., Caroppo, P., Tagliavini, F., Waldo, M. L., Johansson, P. M., Nilsson, C. F., The American Genome Center (TAGC), The FALS Sequencing Consortium, ... Traynor, B. J. (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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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 = "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 {The American Genome Center (TAGC)} and Adelani Adeleye and Camille Alba and Dagmar Bacikova and Hupalo, {Daniel N.} and {McGrath Martinez}, Elisa and Pollard, {Harvey B.} and Gauthaman Sukumar and Soltis, {Anthony R.} and Meila Tuck and Xijun Zhang and Wilkerson, {Mathew D.} and {The FALS Sequencing Consortium} 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 Barbara Castellotti and {de Belleroche}, Jacqueline and Frank Baas and {ten Asbroek}, {Anneloor L. M. A.} and Sapp, {Peter C.} and Diane McKenna-Yasek and McLaughlin, {Russell L.} and Meraida Polak and Seneshaw Asress and Jes{\'u}s Esteban-P{\'e}rez and Mu{\~n}oz-Blanco, {Jos{\'e} Luis} and Zorica Stevic and Sandra D'Alfonso and Letizia Mazzini and Comi, {Giacomo P.} and Bo, {Roberto Del} and Mauro Ceroni and Stella Gagliardi and Giorgia Querin and Cinzia Bertolin and {van Rheenen}, Wouter and Diekstra, {Frank P.} and Rosa Rademakers and {van Blitterswijk}, Marka and Boylan, {Kevin B.} and Giuseppe Lauria and Stefano Duga and Stefania Corti and Cristina Cereda and Lucia Corrado and Gianni Sorar{\`u} and Williams, {Kelly L.} and Nicholson, {Garth A.} and Blair, {Ian P.} 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)} and {The NYGC ALS Consortium} and {The PROSPECT Consortium} and Rowe, {James B.} and Luisa Benussi and Giuliano Binetti and Roberta Ghidoni and Edwin Jabbari and Coralie Viollet and Glass, {Jonathan D.} and Singleton, {Andrew B.} and Vincenzo Silani and Ross, {Owen A.} and Mina Ryten and Ali Torkamani and Toshiko Tanaka and Luigi Ferrucci and Resnick, {Susan M.} and Stuart Pickering-Brown and Brady, {Christopher B.} and Neil Kowal and Hardy, {John A.} and {Van Deerlin}, Vivianna and Vonsattel, {Jean Paul} and Harms, {Matthew B.} and Morris, {Huw R.} and Raffaele Ferrari and Landers, {John E.} and Adriano Chi{\`o} and Gibbs, {J. Raphael} and Dalgard, {Clifton L.} and Scholz, {Sonja W.} and Traynor, {Bryan J.}",

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",

publisher = "Cell Press",

number = "3",

}

Dewan, R, Chia, R, Ding, J, Hickman, RA, Ahmed, S, Sabir, MS, Portley, MK, Tucci, A, Ibáñez, K, Shankaracharya, FNU, Keagle, P, Rossi, G, Caroppo, P, Tagliavini, F, Waldo, ML, Johansson, PM, Nilsson, CF, 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 PROSPECT Consortium, Rowe, JB, Benussi, L, Binetti, G, Ghidoni, R, Jabbari, E, Viollet, C, Glass, JD, Singleton, AB, Silani, V, Ross, OA, Ryten, M, Torkamani, A, Tanaka, T, Ferrucci, L, Resnick, SM, Pickering-Brown, S, Brady, CB, Kowal, N, Hardy, JA, Van Deerlin, V, Vonsattel, JP, Harms, MB, Morris, HR, Ferrari, R, Landers, JE, Chiò, A, Gibbs, JR, Dalgard, CL, Scholz, SW & Traynor, BJ 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 - 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 - The American Genome Center (TAGC)

AU - Adeleye, Adelani

AU - Alba, Camille

AU - Bacikova, Dagmar

AU - Hupalo, Daniel N.

AU - McGrath Martinez, Elisa

AU - Pollard, Harvey B.

AU - Sukumar, Gauthaman

AU - Soltis, Anthony R.

AU - Tuck, Meila

AU - Zhang, Xijun

AU - Wilkerson, Mathew D.

AU - The FALS Sequencing Consortium

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 - Castellotti, Barbara

AU - de Belleroche, Jacqueline

AU - Baas, Frank

AU - ten Asbroek, Anneloor L. M. A.

AU - Sapp, Peter C.

AU - McKenna-Yasek, Diane

AU - McLaughlin, Russell L.

AU - Polak, Meraida

AU - Asress, Seneshaw

AU - Esteban-Pérez, Jesús

AU - Muñoz-Blanco, José Luis

AU - Stevic, Zorica

AU - D'Alfonso, Sandra

AU - Mazzini, Letizia

AU - Comi, Giacomo P.

AU - Bo, Roberto Del

AU - Ceroni, Mauro

AU - Gagliardi, Stella

AU - Querin, Giorgia

AU - Bertolin, Cinzia

AU - van Rheenen, Wouter

AU - Diekstra, Frank P.

AU - Rademakers, Rosa

AU - van Blitterswijk, Marka

AU - Boylan, Kevin B.

AU - Lauria, Giuseppe

AU - Duga, Stefano

AU - Corti, Stefania

AU - Cereda, Cristina

AU - Corrado, Lucia

AU - Sorarù, Gianni

AU - Williams, Kelly L.

AU - Nicholson, Garth A.

AU - Blair, Ian P.

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)

AU - The NYGC ALS Consortium

AU - The PROSPECT Consortium

AU - Rowe, James B.

AU - Benussi, Luisa

AU - Binetti, Giuliano

AU - Ghidoni, Roberta

AU - Jabbari, Edwin

AU - Viollet, Coralie

AU - Glass, Jonathan D.

AU - Singleton, Andrew B.

AU - Silani, Vincenzo

AU - Ross, Owen A.

AU - Ryten, Mina

AU - Torkamani, Ali

AU - Tanaka, Toshiko

AU - Ferrucci, Luigi

AU - Resnick, Susan M.

AU - Pickering-Brown, Stuart

AU - Brady, Christopher B.

AU - Kowal, Neil

AU - Hardy, John A.

AU - Van Deerlin, Vivianna

AU - Vonsattel, Jean Paul

AU - Harms, Matthew B.

AU - Morris, Huw R.

AU - Ferrari, Raffaele

AU - Landers, John E.

AU - Chiò, Adriano

AU - Gibbs, J. Raphael

AU - Dalgard, Clifton L.

AU - Scholz, Sonja W.

AU - Traynor, Bryan J.

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

C2 - 33242422

AN - SCOPUS:85097045939

SN - 0896-6273

VL - 109

SP - 448-460.e4

JO - Neuron

JF - Neuron

IS - 3

ER -

Pathogenic huntingtin repeat expansions in patients with frontotemporal dementia and amyotrophic lateral sclerosis

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