Next Generation Sequencing Analysis in Early Onset Dementia Patients

Alzheimer’s Disease Neuroimaging Initiative

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)243-256
Number of pages14
JournalJournal of Alzheimer's disease : JAD
Volume67
Issue number1
DOIs
Publication statusPublished - 2019

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Dementia
Alzheimer Disease
Apolipoproteins E
Mutation
Genes
Alleles
Genome

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Next Generation Sequencing Analysis in Early Onset Dementia Patients. / Alzheimer’s Disease Neuroimaging Initiative.

In: Journal of Alzheimer's disease : JAD, Vol. 67, No. 1, 2019, p. 243-256.

Research output: Contribution to journalArticle

Alzheimer’s Disease Neuroimaging Initiative. / Next Generation Sequencing Analysis in Early Onset Dementia Patients. In: Journal of Alzheimer's disease : JAD. 2019 ; Vol. 67, No. 1. pp. 243-256.
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title = "Next Generation Sequencing Analysis in Early Onset Dementia Patients",
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.",
author = "{Alzheimer’s Disease Neuroimaging Initiative} and Cristian Bonvicini and Catia Scassellati and Luisa Benussi and {Di Maria}, Emilio and Carlo Maj and Miriam Ciani and Silvia Fostinelli and Anna Mega and Martina Bocchetta and Gaetana Lanzi and Edoardo Giacopuzzi and Sergio Ferraboli and Michela Pievani and Virginia Fedi and Defanti, {Carlo Alberto} and Silvia Giliani and Frisoni, {Giovanni Battista} and Roberta Ghidoni and Massimo Gennarelli",
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T1 - Next Generation Sequencing Analysis in Early Onset Dementia Patients

AU - Alzheimer’s Disease Neuroimaging Initiative

AU - Bonvicini, Cristian

AU - Scassellati, Catia

AU - Benussi, Luisa

AU - Di Maria, Emilio

AU - Maj, Carlo

AU - Ciani, Miriam

AU - Fostinelli, Silvia

AU - Mega, Anna

AU - Bocchetta, Martina

AU - Lanzi, Gaetana

AU - Giacopuzzi, Edoardo

AU - Ferraboli, Sergio

AU - Pievani, Michela

AU - Fedi, Virginia

AU - Defanti, Carlo Alberto

AU - Giliani, Silvia

AU - Frisoni, Giovanni Battista

AU - Ghidoni, Roberta

AU - Gennarelli, Massimo

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

U2 - 10.3233/JAD-180482

DO - 10.3233/JAD-180482

M3 - Article

C2 - 30530974

VL - 67

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EP - 256

JO - Journal of Alzheimer's Disease

JF - Journal of Alzheimer's Disease

SN - 1387-2877

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