TY - JOUR
T1 - Whole genome sequencing analysis reveals post-zygotic mutation variability in monozygotic twins discordant for amyotrophic lateral sclerosis
AU - Tazelaar, Gijs H.P.
AU - Hop, Paul J.
AU - Seelen, Meinie
AU - van Vugt, Joke J.F.A.
AU - van Rheenen, Wouter
AU - Kool, Lindy
AU - van Eijk, Kristel R.
AU - Gijzen, Marleen
AU - Dooijes, Dennis
AU - Moisse, Matthieu
AU - Calvo, Andrea
AU - Moglia, Cristina
AU - Brunetti, Maura
AU - Canosa, Antonio
AU - Nordin, Angelica
AU - Pardina, Jesus S.Mora
AU - Ravits, John
AU - Al-Chalabi, Ammar
AU - Chio, Adriano
AU - McLaughlin, Russell L.
AU - Hardiman, Orla
AU - Van Damme, Philip
AU - de Carvalho, Mamede
AU - Neuwirth, Christoph
AU - Weber, Markus
AU - Andersen, Peter M.
AU - van den Berg, Leonard H.
AU - Veldink, Jan H.
AU - van Es, Michael A.
N1 - Funding Information:
A.A.-C. receives salary support from the National Institute for Health Research (NIHR) Dementia Biomedical Research Unit and Biomedical Research Centre in Mental Health at South London and Maudsley NHS Foundation Trust and King's College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. O.H. is funded by the Health Research Board Clinician Scientist Programme and Science Foundation Ireland. R.L.M is also supported by the Thierry Latran Foundation (ALSIBD) and the ALS Association (2284). The Swedish Brain Foundation (grants nr. 2012-0262, 2012-0305, 2013-0279, 2016-0303 ), the Swedish Science Council (grants nr 2012-3167, 2017-03100 ), the Knut and Alice Wallenberg Foundation (grants nr. 2012.0091, 2014.0305 ), the Bertil Hållsten Foundation, the Ulla-Carin Lindquist Foundation , the Neuroförbundet Association, the Torsten and Ragnar Söderberg Foundation, Umeå University Insamlingsstiftelsen ( 223-2808-12, 223-1881-13, 2.1.12-1605-14 ), Västerbotten County Council, Swedish Brain Power, King Gustaf V:s and Queen Victoria's Freemason's Foundation.
Funding Information:
This study was funded by the Thierry Latran Foundation and the Dutch ALS foundation. Project MinE Belgium was supported by a grant from IWT (n° 140935), the ALS Liga België, the National Lottery of Belgium and the KU Leuven Opening the Future Fund. M.A.v.E. is additionally supported by the Rudolf Magnus Brain Center Talent Fellowship. P.V.D. holds a senior clinical investigatorship of FWO-Vlaanderen and is supported by the E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders, the ALS Liga België and the KU Leuven funds “Een Hart voor ALS,” “Laeversfonds voor ALS Onderzoek” and the “Valéry Perrier Race against ALS Fund.” Several authors of this publication are member of the European Reference Network for Rare Neuromuscular Diseases (ERN-NMD).
Funding Information:
A.A.-C. receives salary support from the National Institute for Health Research (NIHR) Dementia Biomedical Research Unit and Biomedical Research Centre in Mental Health at South London and Maudsley NHS Foundation Trust and King's College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. O.H. is funded by the Health Research Board Clinician Scientist Programme and Science Foundation Ireland. R.L.M is also supported by the Thierry Latran Foundation (ALSIBD) and the ALS Association (2284). The Swedish Brain Foundation (grants nr. 2012-0262, 2012-0305, 2013-0279, 2016-0303), the Swedish Science Council (grants nr 2012-3167, 2017-03100), the Knut and Alice Wallenberg Foundation (grants nr. 2012.0091, 2014.0305), the Bertil Hållsten Foundation, the Ulla-Carin Lindquist Foundation, the Neuroförbundet Association, the Torsten and Ragnar Söderberg Foundation, Umeå University Insamlingsstiftelsen (223-2808-12, 223-1881-13, 2.1.12-1605-14), Västerbotten County Council, Swedish Brain Power, King Gustaf V:s and Queen Victoria's Freemason's Foundation.
Publisher Copyright:
© 2022 The Author(s)
PY - 2023/2
Y1 - 2023/2
N2 - Amyotrophic lateral sclerosis is a heterogeneous, fatal neurodegenerative disease, characterized by motor neuron loss and in 50% of cases also by cognitive and/or behavioral changes. Mendelian forms of ALS comprise approximately 10-15% of cases. The majority is however considered sporadic, but also with a high contribution of genetic risk factors. To explore the contribution of somatic mutations and/or epigenetic changes to disease risk, we performed whole genome sequencing and methylation analyses using samples from multiple tissues on a cohort of 26 monozygotic twins discordant for ALS, followed by in-depth validation and replication experiments. The results of these analyses implicate several mechanisms in ALS pathophysiology, which include a role for de novo mutations, defects in DNA damage repair and accelerated aging.
AB - Amyotrophic lateral sclerosis is a heterogeneous, fatal neurodegenerative disease, characterized by motor neuron loss and in 50% of cases also by cognitive and/or behavioral changes. Mendelian forms of ALS comprise approximately 10-15% of cases. The majority is however considered sporadic, but also with a high contribution of genetic risk factors. To explore the contribution of somatic mutations and/or epigenetic changes to disease risk, we performed whole genome sequencing and methylation analyses using samples from multiple tissues on a cohort of 26 monozygotic twins discordant for ALS, followed by in-depth validation and replication experiments. The results of these analyses implicate several mechanisms in ALS pathophysiology, which include a role for de novo mutations, defects in DNA damage repair and accelerated aging.
KW - Amyotrophic Lateral Sclerosis
KW - Genetic modifiers
KW - Post-zygotic mutations
KW - Repeat expansions
UR - http://www.scopus.com/inward/record.url?scp=85143864996&partnerID=8YFLogxK
U2 - 10.1016/j.neurobiolaging.2022.11.010
DO - 10.1016/j.neurobiolaging.2022.11.010
M3 - Article
C2 - 36521271
AN - SCOPUS:85143864996
SN - 0197-4580
VL - 122
SP - 76
EP - 87
JO - Neurobiology of Aging
JF - Neurobiology of Aging
ER -