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.

额颞叶痴呆 (FTD) 是一种临床和遗传异质性疾病。遗传畸变在多大程度上决定了临床表现仍然难以捉摸。我们通过从德国 FTLD 联盟的不同中心招募 509 名 FTD 患者，调查了遗传原因的范围，并评估了基因型驱动的生物标志物概况、疾病严重程度和临床表现的差异，在这些中心对个人进行了临床评估，包括生物标志物分析。对所有患者进行了外显子组测序和C9orf72重复分析。这些遗传分析的诊断率为 18.1%。C9orf72 ( n  = 47)、GRN ( n  = 26)、MAPT中的致病变异( n  = 11)、TBK1 ( n  = 5)、FUS ( n  = 1) 、TARDBP ( n  = 1) 和CTSF ( n  = 1) 在 FTD 的所有临床亚型中被鉴定。TBK1相关的 FTD 常见，占已解决案例的 5.4%。纯合错义变异的检测证实CTSF是 FTD 基因。ABCA7被确定为单基因 FTD 的候选基因。APOE 等位基因的分布在 FTD 患者和普通人群之间没有显着差异。男性性别与 FTD 行为变异的临床表现弱相关。MAPT患者的发病年龄最低。此外，发现高 CSF 神经丝轻链水平与GRN相关的FTD 相关。我们的研究提供了大规模的回顾性临床遗传学数据，例如 FTD 的疾病表现和进展。这些数据将与咨询患者及其家人相关。