Clinico-genetic findings in 509 frontotemporal dementia patients

• DOI: 10.1038/s41380-021-01271-2
• Publication Date: 2021-10-12T11:19:32Z
• Authors: Matias Wagner; Georg Lorenz; Alexander E. Volk; Theresa Brunet; Dieter Edbauer; Riccardo Berutti; Chen Zhao; Sarah Anderl-Straub; Lars Bertram; Adrian Danek; Marcus Deschauer; Veronika Dill; Klaus Fassbender; Klaus Fliessbach; Katharina S. Götze; Holger Jahn; Johannes Kornhuber; Bernhard Landwehr...; Martin Lauer; Hellmuth Obrig; Johannes Prudlo; Anja Schneider; Matthias L. Schro...; Ingo Uttner; Ruth Vukovich; Jens Wiltfang; Andrea S. Winkler; Qihui Zhou; Albert C. Ludolph; ; Konrad Oexle; Markus Otto; Janine Diehl-Schmid; Juliane Winkelmann
• Keywords: Male; Genotype; 610; tau Proteins; Predictive markers; Article; 03 medical and health sciences; 0302 clinical medicine; Exome Sequencing; Genetics; Humans; ddc:610; Genetik; genetics [C9orf72 Protein]; genetics [Frontotemporal Dementia]; info:eu-repo/classification/ddc/610; Retrospective Studies; info:eu-repo/classification/ddc/570; ddc:610; C9orf72 Protein; Mental Disorders; ddc:; 3. Good health; genetics [tau Proteins]; Article ; Genetics ; Predictive markers ; Psychiatric disorders; Frontotemporal Dementia; Mutation; Psychiatric disorders; Mutation [MeSH] ; C9orf72 Protein/genetics [MeSH] ; Humans [MeSH] ; Predictive markers ; Retrospective Studies [MeSH] ; Exome Sequencing [MeSH] ; Article ; Male [MeSH] ; Genetics ; Genotype [MeSH] ; Psychiatric disorders ; Frontotemporal Dementia/genetics [MeSH] ; tau Proteins/genetics [MeSH]; Biomarkers

AbstractFrontotemporal 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.