1. Clinico-genetic findings in 509 frontotemporal dementia patients
- Author
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Holger Jahn, Theresa Brunet, Marcus Deschauer, Katharina Götze, Lars Bertram, Matias Wagner, Klaus Fassbender, Markus Otto, Johannes Prudlo, Sarah Anderl-Straub, Riccardo Berutti, Andrea Sylvia Winkler, Albert C. Ludolph, Jens Wiltfang, Matthias L. Schroeter, Adrian Danek, Alexander E Volk, Klaus Fliessbach, Martin Lauer, Ruth Vukovich, Hellmuth Obrig, Chen Zhao, Anja Schneider, Qihui Zhou, Konrad Oexle, Georg Lorenz, Bernhard Landwehrmeyer, Juliane Winkelmann, Janine Diehl-Schmid, Ingo Uttner, Veronika Dill, Johannes Kornhuber, and Dieter Edbauer
- Subjects
Oncology ,Male ,medicine.medical_specialty ,Candidate gene ,Genotype ,Population ,tau Proteins ,Predictive markers ,TARDBP ,Article ,Cellular and Molecular Neuroscience ,C9orf72 ,Internal medicine ,mental disorders ,Exome Sequencing ,Genetics ,Medicine ,Humans ,ddc:610 ,education ,Molecular Biology ,genetics [C9orf72 Protein] ,genetics [Frontotemporal Dementia] ,Exome sequencing ,Retrospective Studies ,education.field_of_study ,C9orf72 Protein ,business.industry ,Genetic heterogeneity ,nutritional and metabolic diseases ,medicine.disease ,ddc ,nervous system diseases ,Psychiatry and Mental health ,genetics [tau Proteins] ,Psychiatric disorders ,Frontotemporal Dementia ,Mutation ,Age of onset ,business ,Frontotemporal dementia - 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.
- Published
- 2021
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