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.
| Original language | English |
|---|---|
| Journal | Molecular Psychiatry |
| Volume | 26 |
| Issue number | 10 |
| Pages (from-to) | 5824-5832 |
| Number of pages | 9 |
| ISSN | 1359-4184 |
| DOIs | |
| Publication status | Published - 10.2021 |
Funding
We want to thank Katharina Mayerhanser, Veronika Treffer, Katrin Rading, Marika Pusch, Gertrud Eckstein and Sandy Lösecke for excellent sample handling. Especially, we thank Sarah Stanton for her support in editing this paper. We also thank the Helmholtz Zentrum München NGS core facility for support. The study was partly supported by the Munich Cluster of Systems Neurology (SyNergy). Jens Wiltfang is supported by an Ilídio Pinho professorship, iBiMED (UIDB/04501/2020) at the University of Aveiro, Portugal. This study was supported by the EU Joint Program-Neurodegenerative Diseases networks Genfi-Prox, the German Federal Ministry of Education and Research (FTLDc, the German Research Foundation/DFG (SFB1279), the foundation of the state Baden-Württemberg (D.3830), the Thierry Latran Foundation and the ALS Association).
