Journal Article

DZNE-2021-01580

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Clinico-genetic findings in 509 frontotemporal dementia patients.

Wagner, M. ; Lorenz, G. ; Volk, A. E. ; Brunet, T. ; Edbauer, D.DZNE* ; Berutti, R. ; Zhao, C. ; Anderl-Straub, S. ; Bertram, L. ; Danek, A.Extern* ; Deschauer, M. ; Dill, V. ; Fassbender, K. ; Fliessbach, K.DZNE* ; Götze, K. S. ; Jahn, H. ; Kornhuber, J. ; Landwehrmeyer, B. ; Lauer, M. ; Obrig, H. ; Prudlo, J.DZNE* ; Schneider, A.DZNE* ; Schroeter, M. L. ; Uttner, I. ; Vukovich, R. C.Extern* ; Wiltfang, J.DZNE* ; Winkler, A. S. ; Zhou, Q.DZNE* ; Ludolph, A. C.DZNE* ; consortium, G. F. (Collaboration Author) ; Oexle, K. ; Otto, M. ; Diehl-Schmid, J.Extern* ; Winkelmann, J. (Corresponding author)

2021
Macmillan London

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Please use a persistent id in citations: doi:10.1038/s41380-021-01271-2

Abstract: Frontotemporal dementia (FTD) is a clinically and genetically heterogeneous disorder. To which extent genetic aberrations dictate clinical presentation remains elusive. We investigated the spectrum of genetic causes and assessed the genotype-driven differences in biomarker profiles, disease severity and clinical manifestation by recruiting 509 FTD patients from different centers of the German FTLD consortium where individuals were clinically assessed including biomarker analysis. Exome sequencing as well as C9orf72 repeat analysis were performed in all patients. These genetic analyses resulted in a diagnostic yield of 18.1%. Pathogenic variants in C9orf72 (n = 47), GRN (n = 26), MAPT (n = 11), TBK1 (n = 5), FUS (n = 1), TARDBP (n = 1), and CTSF (n = 1) were identified across all clinical subtypes of FTD. TBK1-associated FTD was frequent accounting for 5.4% of solved cases. Detection of a homozygous missense variant verified CTSF as an FTD gene. ABCA7 was identified as a candidate gene for monogenic FTD. The distribution of APOE alleles did not differ significantly between FTD patients and the average population. Male sex was weakly associated with clinical manifestation of the behavioral variant of FTD. Age of onset was lowest in MAPT patients. Further, high CSF neurofilament light chain levels were found to be related to GRN-associated FTD. Our study provides large-scale retrospective clinico-genetic data such as on disease manifestation and progression of FTD. These data will be relevant for counseling patients and their families.

Keyword(s): C9orf72 Protein: genetics (MeSH) ; Frontotemporal Dementia: genetics (MeSH) ; Genotype (MeSH) ; Humans (MeSH) ; Male (MeSH) ; Mutation (MeSH) ; Retrospective Studies (MeSH) ; Exome Sequencing (MeSH) ; tau Proteins: genetics (MeSH)

Note: CC BY

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Contributing Institute(s):

1. Cell Biology of Neurodegeneration (AG Edbauer)
2. Translational Dementia Research (Bonn) (AG Schneider)
3. Clinical Dementia Research (Rostock /Greifswald) (AG Teipel)
4. Molecular biomarkers for predictive diagnostics of neurodegenerative diseases (AG Wiltfang)
5. Clinical Study Center Ulm (Clinical Study Center Ulm)
6. Patient Studies Bonn (Patient Studies Bonn)
7. Adaptive Immunity in Neurodegeneration (AG Zhou)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)
2. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2021

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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