TY - JOUR
T1 - Underlying genetic variation in familial frontotemporal dementia
T2 - sequencing of 198 patients
AU - Mol, Merel O.
AU - van Rooij, Jeroen G.J.
AU - Wong, Tsz H.
AU - Melhem, Shamiram
AU - Verkerk, Annemieke J.M.H.
AU - Kievit, Anneke J.A.
AU - van Minkelen, Rick
AU - Rademakers, Rosa
AU - Pottier, Cyril
AU - Kaat, Laura Donker
AU - Seelaar, Harro
AU - van Swieten, John C.
AU - Dopper, Elise G.P.
N1 - Funding Information:
This research was funded by Alzheimer Nederland and by The Dutch Research Council ( NWO ).
Funding Information:
The authors are indebted to all the patients who made this study possible. The authors also thank Prof. A.J.M. Rozemuller from the Netherlands Brain Bank for the neuropathologic examination of the cases. This research was funded by Alzheimer Nederland and by The Dutch Research Council (NWO). Ethical assurances: Approval of the study was provided by the Medical Ethics Review Board of the Erasmus Medical Center of Rotterdam (MEC-2009-170). Written informed consent was obtained from all participants or their legal representatives. Brain autopsy was performed in accordance with the Legal and Ethical Code of Conduct of the Netherlands Brain Bank.
Publisher Copyright:
© 2020 The Author(s)
PY - 2021/1
Y1 - 2021/1
N2 - Frontotemporal dementia (FTD) presents with a wide variability in clinical syndromes, genetic etiologies, and underlying pathologies. Despite the discovery of pathogenic variants in several genes, many familial cases remain unsolved. In a large FTD cohort of 198 familial patients, we aimed to determine the types and frequencies of variants in genes related to FTD. Pathogenic or likely pathogenic variants were revealed in 74 (37%) patients, including 4 novel variants. The repeat expansion in C9orf72 was most common (21%), followed by variants in MAPT (6%), GRN (4.5%), and TARDBP (3.5%). Other pathogenic variants were found in VCP, TBK1, PSEN1, and a novel homozygous variant in OPTN. Furthermore, we identified 15 variants of uncertain significance, including a promising variant in TUBA4A and a frameshift in VCP, for which additional research is needed to confirm pathogenicity. The patients without identified genetic cause demonstrated a wide clinical and pathological variety. Our study contributes to the clinical characterization of the genetic subtypes and confirms the value of whole-exome sequencing in identifying novel genetic variants.
AB - Frontotemporal dementia (FTD) presents with a wide variability in clinical syndromes, genetic etiologies, and underlying pathologies. Despite the discovery of pathogenic variants in several genes, many familial cases remain unsolved. In a large FTD cohort of 198 familial patients, we aimed to determine the types and frequencies of variants in genes related to FTD. Pathogenic or likely pathogenic variants were revealed in 74 (37%) patients, including 4 novel variants. The repeat expansion in C9orf72 was most common (21%), followed by variants in MAPT (6%), GRN (4.5%), and TARDBP (3.5%). Other pathogenic variants were found in VCP, TBK1, PSEN1, and a novel homozygous variant in OPTN. Furthermore, we identified 15 variants of uncertain significance, including a promising variant in TUBA4A and a frameshift in VCP, for which additional research is needed to confirm pathogenicity. The patients without identified genetic cause demonstrated a wide clinical and pathological variety. Our study contributes to the clinical characterization of the genetic subtypes and confirms the value of whole-exome sequencing in identifying novel genetic variants.
KW - Familial
KW - Frontotemporal dementia
KW - Genetic screen
KW - Whole-exome sequencing
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U2 - 10.1016/j.neurobiolaging.2020.07.014
DO - 10.1016/j.neurobiolaging.2020.07.014
M3 - Article
C2 - 32843152
AN - SCOPUS:85089728554
SN - 0197-4580
VL - 97
SP - 148.e9-148.e16
JO - Neurobiology of aging
JF - Neurobiology of aging
ER -