Abstract
PurposeTo 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.ResultsPathogenic 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).ConclusionOur 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.
Highlights
The term “frontotemporal dementia” (FTD) describes a clinically and genetically heterogeneous group of disorders sharing progressive degeneration of frontotemporal networks as a common hallmark
Pathogenic and likely pathogenic mutations were identified in 19% of the subjects, including mutations in C9orf[72] (n = 8), GRN (n = 7, one 11-exon macro-deletion) and, more rarely, CHCHD10, TARDBP, SQSTM1 and UBQLN2, but not in MAPT or TBK1
whole-exome sequencing (WES) 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)
Summary
The term “frontotemporal dementia” (FTD) describes a clinically and genetically heterogeneous group of disorders sharing progressive degeneration of frontotemporal networks as a common hallmark. FTD comprises behavioral variant FTD (bvFTD), the semantic variant (svPPA), and the nonfluent variant (nfPPA) of primary progressive aphasia.[1,2,3] behavioral and aphasic presentations of frontotemporal network degeneration can be caused by underlying amyloid pathology, e.g., in behavioral variant AD (bvAD)[4] and logopenic variant PPA (lvPPA).[3] This is in line with several postmortem studies demonstrating that clinically and neuropathologically diagnosed FTD can result from different underlying pathologies (e.g., tau, TDP-43, or amyloid pathology), indicating that multiple pathogenic pathways might result in converging and/or overlapping clinical phenotypes.[5] Corresponding with this complex pathological architecture of FTD, genes in manifold pathways have recently been implicated in its molecular pathogenesis.[6] the full spectrum of neurodegenerative disease (NDD) genes and the relative proportions in which each contributes to the complex genetic architecture of FTD have not yet been systematically explored in a strictly consecutive series and using unbiased sequencing approaches. We hypothesized that mutations are found in a substantial proportion of clinical FTD subjects, even in the Submitted 8 February 2017; accepted 23 May 2017; advance online publication 27 July 2017. doi:10.1038/gim.2017.102
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