Genetic analyses of early-onset Alzheimer\u2019s disease using next generation sequencing

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

doi:10.1038/s41598-019-44848-2

Young Chul Youn, Young Soon Yang + Show 4 more

Open Access

https://doi.org/10.1038/s41598-019-44848-2

Copy DOI

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.

Highlights

Alzheimer disease (AD) is a devastating neurodegenerative disease accounting for 50–75% of all forms of dementia
Mini-Mental State Examination (MMSE)and Clinical Dementia Rating (CDR) scores were 28 and 0.5, respectively, and the patient was definitely diagnosed with Alzheimer’s disease (AD)
presenilin 1 (PSEN1) Gly417Ala was found in a 37-year-old male patient diagnosed with symptoms that overlap between AD and Parkinsonism, followed by progressive language disturbance and behavioral changes with Parkinsonism

Summary

Introduction

Alzheimer disease (AD) is a devastating neurodegenerative disease accounting for 50–75% of all forms of dementia. A recent study demonstrated that PARK2 (p.T240M, p.Q34fs delAG) variants in early-onset PD and MAPT (p.A469T) are associated with de novo EOAD31 Sporadic neurodegenerative diseases, such as PD, AD, multiple system atrophy, Creutzfeldt-Jakob disease (CJD), ALS, and corticobasal degeneration disease, can present similar clinical phenotypes as progressive supranuclear palsy, which may result in a false diagnosis[32,33]. These findings suggest the need for a detailed screening of patients with EOAD to improve differential diagnosis, as may harbor potential causative variants of PD and FTD. An NGS panel of 50 genes described previously[19] was used to evaluated 67 Korean patients with EOAD

Methods

Results

Conclusion