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