Blauwendraat C1, Wilke C2,3, Simón-Sánchez J2,3, Jansen IE4, Reifschneider A5, Capell A5, Haass C5,6,7, Castillo-Lizardo M1, Biskup S8, Maetzler W2,3, Rizzu P1, Heutink P2,4, Synofzik M2,3.
To define the genetic spectrum and relative gene frequencies underlying clinical frontotemporal dementia (FTD).MethodsWe investigated the frequencies and mutations in neurodegenerative disease genes in 121 consecutive FTD subjects using an unbiased, combined sequencing approach, complemented by cerebrospinal fluid Aβ1-42 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.
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).
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.
This paper was published in the Journal of Genetics in Medicine
- Applied Genomics for Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
- Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen Germany.
- Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
- Genome Biology of Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
- Biomedical Center (BMC), Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany.
- Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
- German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany.
- Center for Genomics and Transcriptomics, Tübingen, Germany.