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Blauwendraat, Cornelis; Wilke, Carlo; Simon-Sanchez, Javier; Jansen, Iris E.; Reifschneider, Anika; Capell, Anja; Haass, Christian ORCID: 0000-0002-4869-1627; Castillo-Lizardo, Melissa; Biskup, Saskia; Maetzler, Walter; Rizzu, Patrizia; Heutink, Peter; Synofzik, Matthis (2018): The wide genetic landscape of clinical frontotemporal dementia: systematic combined sequencing of 121 consecutive subjects. In: Genetics in Medicine, Vol. 20, No. 2: pp. 240-249
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Purpose: To define the genetic spectrum and relative gene frequencies underlying clinical frontotemporal dementia (FTD). Methods: We investigated the frequencies and mutations in neurodegenerative disease genes in 121 consecutive FTD subjects using an unbiased, combined sequencing approach, complemented by cerebrospinal fluid A beta(1-42) and serum progranulin measurements. Subjects were screened for C9orf72 repeat expansions, GRN and MAPT mutations, and, if negative, mutations in other neurodegenerative disease genes, by whole-exome sequencing (WES) (n = 108), including WES-based copy-number variant (CNV) analysis. Results: Pathogenic and likely pathogenic mutations were identified in 19% of the subjects, including mutations in C9orf72 (n = 8), GRN (n = 7, one 11-exon macro-deletion) and, more rarely, CHCHD10, TARDBP, SQSTM1 and UBQLN2 (each n = 1), but not in MAPT or TBK1. WES also unraveled pathogenic mutations in genes not commonly linked to FTD, including mutations in Alzheimer (PSEN1, PSEN2), lysosomal (CTSF, 7-exon macro-deletion) and cholesterol homeostasis pathways (CYP27A1). Conclusion: Our unbiased approach reveals a wide genetic spectrum underlying clinical FTD, including 11% of seemingly sporadic FTD. It unravels several mutations and CNVs in genes and pathways hitherto not linked to FTD. This suggests that clinical FTD might be the converging downstream result of a delicate susceptibility of frontotemporal brain networks to insults in various pathways.