title: Targeted high-throughput sequencing identifies a TARDBP mutation as a cause of early-onset FTD without motor neuron disease.
abstract: Targeted high-throughput sequencing of many amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD) genes in parallel has the potential to reveal novel ALS- and/or FTD-phenotypes and to provide missing links on the ALS-FTD continuum. For example, although the 43-kDa transactive response DNA binding protein is the major pathologic hallmark linking ALS and FTD, mutations in the gene encoding 43-kDa transactive response DNA binding protein (TARDBP) have been appreciated only as a cause of ALS-phenotypes, but not yet of pure FTD. Thus, the genetic link is not yet well substantiated that TARDBP mutations can cause the full spectrum of the ALS-FTD continuum. High-throughput sequencing of 18 ALS and FTD genes in an index patient presenting with early-onset pure (behavioral) FTD and a positive family history for ALS revealed an established TARDBP mutation, A382T. This finding demonstrates that a TARDPB mutation can cause early-onset pure FTD without evidence for ALS even in advanced FTD disease stages. Moreover, it indicates that TARDPB screening might be considered even in young patients with "pure" neuropsychiatric disturbances and without evidence of neurodegenerative disease in the parental generation.
authors.affiliation: Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Baden-Württemberg, Germany; German Research Center for Neurodegenerative Diseases (DZNE), Tübingen, Baden-Württemberg, Germany. Electronic address: matthis.synofzik@uni-tuebingen.de.
authors.forename: Matthis
authors.initials: M
authors.lastname: Synofzik
authors.affiliation: Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University, Munich, Bavaria, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Born
authors.affiliation: Department of Nuclear Medicine, Ludwig-Maximilians-University, Munich, Bavaria, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Rominger
authors.affiliation: Department of Neuroradiology, Ludwig-Maximilians-University, Munich, Bavaria, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Lummel
authors.affiliation: Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Baden-Württemberg, Germany; German Research Center for Neurodegenerative Diseases (DZNE), Tübingen, Baden-Württemberg, Germany.
authors.forename: Ludger
authors.initials: L
authors.lastname: Schöls
authors.affiliation: Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Baden-Württemberg, Germany; German Research Center for Neurodegenerative Diseases (DZNE), Tübingen, Baden-Württemberg, Germany; CeGaT GmbH, Center for Genomics and Transcriptomics, Tübingen, Baden-Württemberg, Germany.
authors.forename: Saskia
authors.initials: S
authors.lastname: Biskup
authors.affiliation: Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University, Munich, Bavaria, Germany.
authors.forename: Cornelius
authors.initials: C
authors.lastname: Schüle
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University of Tübingen, Baden-Württemberg, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Grasshoff
authors.affiliation: Department of Neurology with Friedrich-Baur-Institute, Ludwig-Maximilians-University, Munich, Bavaria, Germany; German Research Center for Neurodegenerative Diseases (DZNE), Munich, Bavaria, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Bavaria, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Klopstock
authors.affiliation: Department of Neurology with Friedrich-Baur-Institute, Ludwig-Maximilians-University, Munich, Bavaria, Germany.
authors.forename: Christopher
authors.initials: C
authors.lastname: Adamczyk
mesh_terms: D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D057180:Frontotemporal Dementia / Q000175:diagnosis / Q000235:genetics*; D005820:Genetic Testing / Q000379:methods; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D016472:Motor Neuron Disease; D009154:Mutation; D049268:Positron-Emission Tomography
chemical_list: D004268:DNA-Binding Proteins
keywords: Amyotrophic lateral sclerosis; Frontotemporal dementia; Frontotemporal lobe dementia; Genetics; Next-generation sequencing; Panel diagnostics; TDP-43