title: Pilot whole-exome sequencing of a German early-onset Alzheimer's disease cohort reveals a substantial frequency of PSEN2 variants.
abstract: Early-onset Alzheimer's disease (EOAD) accounts for 1%-2% of all Alzheimer's disease (AD) subjects, with large variation in the reported genetic contribution of known dementia genes. In this pilot study, we genetically characterized a German EOAD cohort (23 subjects) by whole-exome sequencing, capturing variants in all recognized AD and frontotemporal dementia genes. After variant filtering, we identified 7 events of altogether 6 different rare variants in 6 subjects, including 4 novel variants. Four of the 6 variants, observed in 5 different index subjects (5/23 = 22%), were considered to be possibly pathogenic. These included 2 presenilin 2 (PSEN2) variants (p.N141I-previously denoted as a Volga German variant, observed in 2 index subjects; and p.L238P), 1 amyloid precursor protein (p.I716M), and 1 presenilin 1 (ΔE9). Using a control exome data set of 96 ethnically matched neurodegenerative disease controls (Parkinson's disease), we identified only 1 variant (PSEN2 p.T18M) (1%), demonstrating a significantly higher mutational burden in the EOAD group (p > 0.0001). Our findings demonstrate a substantial frequency of variants in dementia genes in EOAD, including several seemingly "sporadic" subjects. This indicates that heritability in EOAD might be higher than assumed. The finding of 3 subjects carrying potential pathogenic PSEN2 variants suggests that, in specific populations PSEN2 variants might be as frequent as (or more frequent than) presenilin 1, for example, in German populations which are influenced by Volga German heritage. Variants in AD genes were also associated with rare phenotypes such as frontal AD or primary progressive aphasia, demonstrating the need to screen AD genes in frontotemporal dementia-like phenotypes.
authors.affiliation: Applied Genomics for Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
authors.forename: Cornelis
authors.initials: C
authors.lastname: Blauwendraat
authors.affiliation: Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
authors.forename: Carlo
authors.initials: C
authors.lastname: Wilke
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands; Genome Biology of Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
authors.forename: Iris E
authors.initials: IE
authors.lastname: Jansen
authors.affiliation: Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Schulte
authors.affiliation: Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; Genome Biology of Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
authors.forename: Javier
authors.initials: J
authors.lastname: Simón-Sánchez
authors.affiliation: Department of Psychiatry and Psychotherapy and Geriatric Center, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Florian G
authors.initials: FG
authors.lastname: Metzger
authors.affiliation: Magnetic Resonance Research Group, Department of Diagnostic and Interventional Neuroradiology, University, Hospital Tübingen, Tübingen, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Bender
authors.affiliation: Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gasser
authors.affiliation: Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Maetzler
authors.affiliation: Applied Genomics for Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Rizzu
authors.affiliation: Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands; Genome Biology of Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Heutink
authors.affiliation: Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany. Electronic address: matthis.synofzik@uni-tuebingen.de.
authors.forename: Matthis
authors.initials: M
authors.lastname: Synofzik
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics*; D015331:Cohort Studies; D059472:Exome / Q000235:genetics*; D005260:Female; D057180:Frontotemporal Dementia / Q000235:genetics; D056726:Genetic Association Studies; D014644:Genetic Variation / Q000235:genetics*; D005858:Germany; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010865:Pilot Projects; D053766:Presenilin-2 / Q000235:genetics*; D017422:Sequence Analysis, DNA / Q000379:methods*
chemical_list: C508861:PSEN2 protein, human; D053766:Presenilin-2
keywords: Alzheimer's disease; Early-onset dementia; Exome sequencing; Frontotemporal dementia; PSEN2; Volga German N141I