eprintid: 10063670
rev_number: 36
eprint_status: archive
userid: 608
dir: disk0/10/06/36/70
datestamp: 2018-12-10 11:40:30
lastmod: 2021-09-17 22:14:51
status_changed: 2019-02-06 14:42:39
type: article
metadata_visibility: show
creators_name: Bonvicini, C
creators_name: Scassellati, C
creators_name: Benussi, L
creators_name: Di Maria, E
creators_name: Maj, C
creators_name: Ciani, M
creators_name: Fostinelli, S
creators_name: Mega, A
creators_name: Bocchetta, M
creators_name: Lanzi, G
creators_name: Giacopuzzi, E
creators_name: Ferraboli, S
creators_name: Pievani, M
creators_name: Fedi, V
creators_name: Defanti, CA
creators_name: Giliani, S
creators_name: Ghidoni, R
creators_name: Frisoni, GB
creators_name: Gennarelli, M
title: Next Generation Sequencing Analysis in Early Onset Dementia Patients
ispublished: pub
divisions: UCL
divisions: B02
divisions: C07
divisions: D07
divisions: F86
keywords: Alzheimer’s disease, common variants, early onset dementia, frontotemporal dementia, Lewy body dementia, next generation sequencing, rare mutations
note: This article is published online with Open Access and distributed under the terms of the Creative Commons Attribution Non-Commercial License (CC BY-NC 4.0). http://creativecommons.org/licenses/by/4.0/
abstract: BACKGROUND: Early onset dementias (EOD) are rare neurodegenerative dementias that present before 65 years. Genetic factors have a substantially higher pathogenetic contribution in EOD patients than in late onset dementia. OBJECTIVE: To identify known and/or novel rare variants in major candidate genes associated to EOD by high-throughput sequencing. Common-risk variants of apolipoprotein E (APOE) and prion protein (PRNP) genes were also assessed. METHODS: We studied 22 EOD patients recruited in Memory Clinics, in the context of studies investigating genetic forms of dementia. Two methodological approaches were applied for the target-Next Generation Sequencing (NGS) analysis of these patients. In addition, we performed progranulin plasma dosage, C9Orf72 hexanucleotide repeat expansion analysis, and APOE genotyping. RESULTS: We detected three rare known pathogenic mutations in the GRN and PSEN2 genes and eleven unknown-impact mutations in the GRN, VCP, MAPT, FUS, TREM2, and NOTCH3 genes. Six patients were carriers of only common risk variants (APOE and PRNP), and one did not show any risk mutation/variant. Overall, 69% (n = 9) of our early onset Alzheimer’s disease (EAOD) patients, compared with 34% (n = 13) of sporadic late onset Alzheimer’s disease (LOAD) patients and 27% (n = 73) of non-affected controls (ADNI, whole genome data), were carriers of at least two rare/common risk variants in the analyzed candidate genes panel, excluding the full penetrant mutations. CONCLUSION: This study suggests that EOD patients without full penetrant mutations are characterized by higher probability to carry polygenic risk alleles that patients with LOAD forms. This finding is in line with recently reported evidence, thus suggesting that the genetic risk factors identified in LOAD might modulate the risk also in EOAD.
date: 2019-01-08
date_type: published
publisher: IOS Press
official_url: http://dx.doi.org/10.3233/JAD-180482
oa_status: green
full_text_type: pub
language: eng
primo: open
primo_central: open_green
article_type_text: Journal Article
verified: verified_manual
elements_id: 1607168
doi: 10.3233/JAD-180482
lyricists_name: Bocchetta, Martina
lyricists_name: Fox, Nicholas
lyricists_id: MBOCC01
lyricists_id: NCIFO25
actors_name: Bocchetta, Martina
actors_id: MBOCC01
actors_role: owner
full_text_status: public
publication: Journal of Alzheimer's Disease
volume: 67
number: 1
pagerange: 243-256
issn: 1387-2877
citation:        Bonvicini, C;    Scassellati, C;    Benussi, L;    Di Maria, E;    Maj, C;    Ciani, M;    Fostinelli, S;                                                 ... Gennarelli, M; + view all <#>        Bonvicini, C;  Scassellati, C;  Benussi, L;  Di Maria, E;  Maj, C;  Ciani, M;  Fostinelli, S;  Mega, A;  Bocchetta, M;  Lanzi, G;  Giacopuzzi, E;  Ferraboli, S;  Pievani, M;  Fedi, V;  Defanti, CA;  Giliani, S;  Ghidoni, R;  Frisoni, GB;  Gennarelli, M;   - view fewer <#>    (2019)    Next Generation Sequencing Analysis in Early Onset Dementia Patients.                   Journal of Alzheimer's Disease , 67  (1)   pp. 243-256.    10.3233/JAD-180482 <https://doi.org/10.3233/JAD-180482>.       Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/10063670/10/Bocchetta%20VoR%20jad_2019_67-1_jad-67-1-jad180482_jad-67-jad180482.pdf