Genetic analyses of early-onset Alzheimer’s disease using next generation sequencing

Vo Van Giau, Eva Bagyinszky, Young Soon Yang, Young Chul Youn, Seong Soo A. An, Sang Yun Kim

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Alzheimer’s disease (AD) is the most common type of neurodegenerative dementia, but the cause of AD remained poorly understood. Many mutations in the amyloid precursor protein (APP) and presenilin 1 and 2 (PSEN1 and PSEN2) have been reported as the pathogenic causes of early-onset AD (EOAD), which accounts for up to 5% of all AD cases. In this study, we screened familiar/de novo EOAD (n = 67) samples by next-generation sequencing (NGS) of a 50-gene panel, which included causative and possible pathogenic variants linked to neurodegenerative disorders. Remarkably, three missense mutations in PSEN1 (T119I, G209A, and G417A) and one known variant in PSEN2 (H169N) were discovered in 6% of the cases. Additionally, 67 missense mutations in susceptibility genes for late-onset AD were identified, which may be involved in cholesterol transport, inflammatory response, and β-amyloid modulation. We identified 70 additional novel and missense variants in other genes, such as MAPT, GRN, CSF1R, and PRNP, related to neurodegenerative diseases, which may represent overlapping clinical and neuropathological features with AD. Extensive genetic screening of Korean patients with EOAD identified multiple rare variants with potential roles in AD pathogenesis. This study suggests that individuals diagnosed with AD should be screened for other neurodegenerative disease-associated genes. Our findings expand the classic set of genes involved in neurodegenerative pathogenesis, which should be screened for in clinical trials. Main limitation of this study was the absence of functional assessment for possibly and probably pathogenic variants. Additional issues were that we could not perform studies on copy number variants, and we could not verify the segregation of mutations.

Original languageEnglish
Article number8368
JournalScientific Reports
Volume9
Issue number1
DOIs
StatePublished - 1 Dec 2019

Fingerprint

Alzheimer Disease
Neurodegenerative Diseases
Genes
Missense Mutation
Presenilin-2
Presenilin-1
Mutation
Amyloid beta-Protein Precursor
Genetic Testing
Amyloid
Dementia
Cholesterol
Clinical Trials

Cite this

Giau, Vo Van ; Bagyinszky, Eva ; Yang, Young Soon ; Youn, Young Chul ; An, Seong Soo A. ; Kim, Sang Yun. / Genetic analyses of early-onset Alzheimer’s disease using next generation sequencing. In: Scientific Reports. 2019 ; Vol. 9, No. 1.
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Genetic analyses of early-onset Alzheimer’s disease using next generation sequencing. / Giau, Vo Van; Bagyinszky, Eva; Yang, Young Soon; Youn, Young Chul; An, Seong Soo A.; Kim, Sang Yun.

In: Scientific Reports, Vol. 9, No. 1, 8368, 01.12.2019.

Research output: Contribution to journalArticle

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T1 - Genetic analyses of early-onset Alzheimer’s disease using next generation sequencing

AU - Giau, Vo Van

AU - Bagyinszky, Eva

AU - Yang, Young Soon

AU - Youn, Young Chul

AU - An, Seong Soo A.

AU - Kim, Sang Yun

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AB - Alzheimer’s disease (AD) is the most common type of neurodegenerative dementia, but the cause of AD remained poorly understood. Many mutations in the amyloid precursor protein (APP) and presenilin 1 and 2 (PSEN1 and PSEN2) have been reported as the pathogenic causes of early-onset AD (EOAD), which accounts for up to 5% of all AD cases. In this study, we screened familiar/de novo EOAD (n = 67) samples by next-generation sequencing (NGS) of a 50-gene panel, which included causative and possible pathogenic variants linked to neurodegenerative disorders. Remarkably, three missense mutations in PSEN1 (T119I, G209A, and G417A) and one known variant in PSEN2 (H169N) were discovered in 6% of the cases. Additionally, 67 missense mutations in susceptibility genes for late-onset AD were identified, which may be involved in cholesterol transport, inflammatory response, and β-amyloid modulation. We identified 70 additional novel and missense variants in other genes, such as MAPT, GRN, CSF1R, and PRNP, related to neurodegenerative diseases, which may represent overlapping clinical and neuropathological features with AD. Extensive genetic screening of Korean patients with EOAD identified multiple rare variants with potential roles in AD pathogenesis. This study suggests that individuals diagnosed with AD should be screened for other neurodegenerative disease-associated genes. Our findings expand the classic set of genes involved in neurodegenerative pathogenesis, which should be screened for in clinical trials. Main limitation of this study was the absence of functional assessment for possibly and probably pathogenic variants. Additional issues were that we could not perform studies on copy number variants, and we could not verify the segregation of mutations.

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