Analysis of 50 Neurodegenerative Genes in Clinically Diagnosed Early-Onset Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD), Parkinson’s disease (PD), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), and prion diseases have a certain degree of clinical, pathological, and molecular overlapping. Previous studies revealed that many causative mutations in AD, PD, and FTD/ALS genes could be found in clinical familial and sporadic AD. To further elucidate the missing heritability in early-onset Alzheimer’s disease (EOAD), we genetically characterized a Thai EOAD cohort by Next-Generation Sequencing (NGS) with a high depth of coverage, capturing variants in 50 previously recognized AD and other related disorders’ genes. A novel mutation, APP p.V604M, and the known causative variant, PSEN1 p.E184G, were found in two of the familiar cases. Remarkably, among 61 missense variants were additionally discovered from 21 genes out of 50 genes, six potential mutations including MAPT P513A, LRRK2 p.R1628P, TREM2 p.L211P, and CSF1R (p.P54Q and pL536V) may be considered to be probably/possibly pathogenic and risk factors for other dementia leading to neuronal degeneration. All allele frequencies of the identified missense mutations were compared to 622 control individuals. Our study provides initial evidence that AD and other neurodegenerative diseases may represent shades of the same disease spectrum, and consideration should be given to offer exactly embracing genetic testing to patients diagnosed with EOAD. Our results need to be further confirmed with a larger cohort from this area.

Association of rare variants in neurodegenerative genes with familial Alzheimer’s disease

“…Recent studies identified that rare variants in several GWAS loci of AD were segregated in LOAD families and may confer risk of AD. [10][11][12] Pathogenic mutations of FTD and PD related genes were presented in dementia patients or families that formerly diagnosed of AD, 19,20 suggesting that rare, pathogenic variants of neurodegenerative genes other than APP, PSEN1 and PSEN2 may account for etiology of the remaining AD families. In this study, we analyzed the association of rare variants in neurodegenerative diseases genes as well as APOE in a Chinese FAD cohort.…”

Pathogenic PSEN1 Glu184Gly Mutation in a Family from Thailand with Probable Autosomal Dominant Early Onset Alzheimer’s Disease

“…Complex genetic investigation by next generation sequencing (NGS) was performed on the proband patient. Targeted NGS approaches were carried out with a panel of 50 causative and risk factor genes in neurodegenerative diseases by Theragen Etex Bio Institute on an IonProton device [20]. The standard Sanger sequencing verified the NGS data by BioNeer Inc. (http://eng.bioneer.com/home.aspx, Bioneer Inc., Daejeon, Korea).…”

“…Additional symptoms, such as Parkinsonism, epilepsy, and language and behavioral impairment may also be prominent in EOAD [17]. Interestingly, de novo cases of AD mutations were also reported without prior family history or any affected family members [2,[18][19][20]. In this study, a pathogenic PSEN1 p.Glu184Gly (g.14:73659354 A>G; c.551A>G; p.E184G) mutation was discovered in an EOAD patient from a Thai family, noted as the first case in Asia.…”

“…In this study, a pathogenic PSEN1 p.Glu184Gly (g.14:73659354 A>G; c.551A>G; p.E184G) mutation was discovered in an EOAD patient from a Thai family, noted as the first case in Asia. Structural characterization using 3D protein prediction was also carried out to understand the putative pathogenic mechanisms of this mutation [20].…”

Correspondence Between Cognitive and Audiological Evaluations Among the Elderly: A Preliminary Report of an Audiological Screening Model of Subjects at Risk of Cognitive Decline With Slight to Moderate Hearing Loss

“…Exclusion criteria were lack of cooperation, life-threatening diseases, psychotropic therapies, history of disabling cardiovascular diseases, ictus or other potential life-threatening conditions, myocardial infarction, transient ischemic attacks or stroke, familiarity of neurodegenerative processes, or in advanced stages of disease. Patients with a history or family history of neurodegenerative diseases were excluded to avoid the contribution of early-onset diseases, which typically have a genetic etiology (Giau et al, 2019). Additionally, adults with hearing aids or cochlear implants were also excluded to avoid interference of digital devices with the acoustic properties of the auditory stimuli, which could significantly modify the SNR (Gallo and Castiglione, 2019).…”