The Whole Exome Sequencing Clarifies the Genotype- Phenotype Correlations in Patients with Early-Onset Dementia

Xu, Yao; Liu, Xiaoli; Shen, Jun; Tian, Wen; Fang, Rong; Li, Binyin; Ma, Jianfang; Cao, Li; Chen, Shengdi; Li, Guanjun; Tang, Huidong

doi:10.14336/ad.2018.0208

Cited by 28 publications

(21 citation statements)

References 44 publications

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“…The PARK7 gene encodes for a chaperone molecule localized in the nucleus and cytoplasm of both neuronal and glial cells, and it seems to be also implicated in oxidative stress. Thus, experimental evidences suggest that PARK7 mutations compromise the chaperone function, leading to a toxic buildup of misfolded or damaged proteins and eventually to cell death [58]; other reports described defects in specific oxidative stress processes and alterations in mitochondrial functions [58,59]. Of note, the complex relationship between energy metabolism and neurodegenerative disorders, including FTD, is one of the most studied topics [60,61].…”

Section: Discussionmentioning

confidence: 99%

The Missing Heritability of Sporadic Frontotemporal Dementia: New Insights from Rare Variants in Neurodegenerative Candidate Genes

Ciani

Bonvicini

Scassellati

et al. 2019

IJMS

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Frontotemporal dementia (FTD) is a common form of dementia among early-onset cases. Several genetic factors for FTD have been revealed, but a large proportion of FTD cases still have an unidentified genetic origin. Recent studies highlighted common pathobiological mechanisms among neurodegenerative diseases. In the present study, we investigated a panel of candidate genes, previously described to be associated with FTD and/or other neurodegenerative diseases by targeted next generation sequencing (NGS). We focused our study on sporadic FTD (sFTD), devoid of disease-causing mutations in GRN, MAPT and C9orf72. Since genetic factors have a substantially higher pathogenetic contribution in early onset patients than in late onset dementia, we selected patients with early onset (<65 years). Our study revealed that, in 50% of patients, rare missense potentially pathogenetic variants in genes previously associated with Alzheimer’s disease, Parkinson disease, amyotrophic lateral sclerosis and Lewy body dementia (GBA, ABCA7, PARK7, FUS, SORL1, LRRK2, ALS2), confirming genetic pleiotropy in neurodegeneration. In parallel, a synergic genetic effect on FTD is suggested by the presence of variants in five different genes in one single patient. Further studies employing genome-wide approaches might highlight pathogenic variants in novel genes that explain the still missing heritability of FTD.

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Section: Discussionmentioning

confidence: 99%

The Missing Heritability of Sporadic Frontotemporal Dementia: New Insights from Rare Variants in Neurodegenerative Candidate Genes

Ciani

Bonvicini

Scassellati

et al. 2019

IJMS

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“…Because the aging population in most Asian countries is increasing, determining the initial pathological change is a key issue for AD research and treatment. Genetic analysis helps with AD diagnosis, evaluation of the pathogenesis, and finding suitable therapeutic targets in AD [15].…”

Section: Discussionmentioning

confidence: 99%

“…EOAD cases with PSEN1 mutations usually occur at 40-60 years of age, but several PSEN1 mutations have also been reported to be associated with very early-onset AD (vEOAD; <35 years of age) [14]. Nonetheless, there are still mutations that remain unidentified along with the rarely reported de novo mutations [15]. In this study, we aimed to present the phenotypic and genetic analysis of three Chinese EOAD families.…”

mentioning

confidence: 99%

Two Novel Mutations and a de novo Mutation in PSEN1 in Early-onset Alzheimer’s Disease

Yang

Zhang

et al. 2019

Aging and disease

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Presenilin 1 ( PSEN1 ), presenilin 2 ( PSEN2 ), and amyloid precursor protein ( APP ) mutations are responsible for autosomal dominant early-onset Alzheimer’s disease (AD-EOAD). To analyze the phenotypes and genotypes of EOAD patients, we performed comprehensive clinical assessments as well as mutation screening of PSEN1 , PSEN2 , and exons 16 and 17 of APP by Sanger sequencing in the three Chinese EOAD families. We identified two novel mutations of PSEN1 (Y256N and H214R) in samples from these families, and a de novo mutation of PSEN1 (G206V) in a patient with very early-onset sporadic Alzheimer’s disease. A combination of bioinformatics tools based on evolutionary, structural and computational methods predicted that the mutations were all deleterious. These findings suggest that PSEN1 Y256N, H214R, and G206V need to be considered as potential causative mutations in EOAD patients. Further functional studies are needed to evaluate the roles of these mutations in the pathogenesis of AD.

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“…A further significant contribution toward the knowledge of genetic FTD background came from the “rare-variants theory”: rare variants widespread in the genome could represent the missing genetic components for complex diseases. Interestingly, these variants can have determining effects on clinical phenotype, in terms of severity and earlier onset (Xu et al, 2018).…”

Section: Next-generation Sequencing and The “Rare-variants Theory”mentioning

confidence: 99%

“…A WES study was conducted to perform a genetic exploration in patients with early onset forms of dementia, including FTD. Specifically, Xu et al (2018) focused on 89 dementia-related causing and susceptible genes, identifying known pathogenic mutations in PSEN1 (Presenilin 1) and MAPT , and one novel pathogenic variant in the Amyloid beta precursor protein ( APP ) gene. The authors also revealed that all the identified mutations caused dementia with an earlier age of onset and a more rapid disease progression (Xu et al, 2018).…”

Section: Next-generation Sequencing and The “Rare-variants Theory”mentioning

confidence: 99%

Genome Wide Association Study and Next Generation Sequencing: A Glimmer of Light Toward New Possible Horizons in Frontotemporal Dementia Research

et al. 2019

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Frontotemporal Dementia (FTD) is a focal neurodegenerative disease, with a strong genetic background, that causes early onset dementia. The present knowledge about the risk loci and causative mutations of FTD mainly derives from genetic linkage analysis, studies of candidate genes, Genome-Wide Association Studies (GWAS) and Next-Generation Sequencing (NGS) applications. In this review, we report recent insights into the genetics of FTD, and, specifically, the results achieved thanks to GWAS and NGS approaches. Linkage studies of large FTD pedigrees have prompted the identification of causal mutations in different genes: mutations in C9orf72 , MAPT , and GRN genes explain the large majority of cases with a high family history of the disease. In cases with a less clear inheritance, GWAS and NGS have contributed to further understand the genetic picture of FTD. GWAS identified several common genetic variants with a modest risk effect. Of interest, many of these variants are in genes belonging to the endo-lysosomal pathway, the immune response and neuronal survival. On the opposite, the NGS approach allowed the identification of rare variants with a strong risk effect. These variants were identified in known FTD-associated genes and again in genes involved in the endo-lysosomal pathway and in the immune response. Interestingly, both approaches demonstrated that several genes are associated to multiple neurodegenerative disorders including FTD. Thanks to these complementary approaches, the genetic picture of FTD is becoming more clear and novel key molecular processes are emerging. This will foster opportunities to move toward prevention and therapy for this incurable disease.

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The Whole Exome Sequencing Clarifies the Genotype- Phenotype Correlations in Patients with Early-Onset Dementia

Cited by 28 publications

References 44 publications

The Missing Heritability of Sporadic Frontotemporal Dementia: New Insights from Rare Variants in Neurodegenerative Candidate Genes

The Missing Heritability of Sporadic Frontotemporal Dementia: New Insights from Rare Variants in Neurodegenerative Candidate Genes

Two Novel Mutations and a de novo Mutation in PSEN1 in Early-onset Alzheimer’s Disease

Genome Wide Association Study and Next Generation Sequencing: A Glimmer of Light Toward New Possible Horizons in Frontotemporal Dementia Research

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