Pilot whole-exome sequencing of a German early-onset Alzheimer's disease cohort reveals a substantial frequency of PSEN2 variants

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 sequenc...

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Vydáno v:Neurobiology of aging Ročník 37; s. 208.e11 - 208.e17
Hlavní autoři: Blauwendraat, Cornelis, Wilke, Carlo, Jansen, Iris E., Schulte, Claudia, Simón-Sánchez, Javier, Metzger, Florian G., Bender, Benjamin, Gasser, Thomas, Maetzler, Walter, Rizzu, Patrizia, Heutink, Peter, Synofzik, Matthis
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States Elsevier Inc 01.01.2016
Témata:
Aged
Alzheimer Disease - genetics
Alzheimer's disease
Cohort Studies
Early-onset dementia
Exome - genetics
Exome sequencing
Female
Frontotemporal dementia
Frontotemporal Dementia - genetics
Genetic Association Studies
Genetic Variation - genetics
Germany
Humans
Internal Medicine
Male
Middle Aged
Mutation
Neurology
Pilot Projects
Presenilin-2 - genetics
PSEN2
Sequence Analysis, DNA - methods
Volga German N141I
Germany
PSEN2
Early-onset dementia
Volga German N141I
Frontotemporal dementia
Alzheimer's disease
Exome sequencing
ISSN:0197-4580, 1558-1497
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Shrnutí: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.
Bibliografie:ObjectType-Article-1
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ISSN:0197-4580
1558-1497
DOI:10.1016/j.neurobiolaging.2015.09.016