Clinico-genetic findings in 509 frontotemporal dementia patients

失智症 C9orf72 痴呆 生物标志物 发病年龄 人口 医学 肿瘤科 遗传学 心理学 内科学
作者
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 Götze,Holger Jahn,Johannes Kornhuber,Bernhard Landwehrmeyer,Martin Lauer,Hellmuth Obrig,Johannes Prudlo,Anja Schneider,Matthias L. Schroeter,Ingo Uttner,Ruth Vukovich,Jens Wiltfang,Andrea Sylvia Winkler,Qihui Zhou,Albert C. Ludolph,Konrad Oexle,Markus Otto,Janine Diehl-Schmid,Juliane Winkelmann
出处
期刊:Molecular Psychiatry [Springer Nature]
卷期号:26 (10): 5824-5832 被引量:4
标识
DOI:10.1038/s41380-021-01271-2
摘要

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.
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